15 research outputs found
GU81, a VEGFR2 antagonist peptoid, enhances the anti-tumor activity of doxorubicin in the murine MMTV-PyMT transgenic model of breast cancer
<p>Abstract</p> <p>Background</p> <p>Vascular endothelial growth factor (VEGF) is a primary stimulant of angiogenesis under physiological and pathological conditions. Anti-VEGF therapy is a clinically proven strategy for the treatment of a variety of cancers including colon, breast, lung, and renal cell carcinoma. Since VEGFR2 is the dominant angiogenic signaling receptor, it has become an important target in the development of novel anti-angiogenic therapies. We have reported previously the development of an antagonistic VEGFR2 peptoid (GU40C4) that has promising anti-angiogenic activity <it>in vitro </it>and <it>in vivo</it>.</p> <p>Methods</p> <p>In the current study, we utilize a derivative of GU40C4, termed GU81 in therapy studies. GU81 was tested alone or in combination with doxorubicin for <it>in vivo </it>efficacy in the MMTV-PyMT transgenic model of breast cancer.</p> <p>Results</p> <p>The derivative GU81 has increased <it>in vitro </it>efficacy compared to GU40C4. Single agent therapy (doxorubicin or GU81 alone) had no effect on tumor weight, histology, tumor fat content, or tumor growth index. However, GU81 is able to significantly to reduce total vascular area as a single agent. GU81 used in combination with doxorubicin significantly reduced tumor weight and growth index compared to all other treatment groups. Furthermore, treatment with combination therapy significantly arrested tumor progression at the premalignant stage, resulting in increased tumor fat content. Interestingly, treatment with GU81 alone increased tumor-VEGF levels and macrophage infiltration, an effect that was abrogated when used in combination with doxorubicin.</p> <p>Conclusion</p> <p>This study demonstrates the VEGFR2 antagonist peptoid, GU81, enhances the anti-tumor activity of doxorubicin in spontaneous murine MMTV-PyMT breast tumors.</p
Cytokine Levels Correlate with Immune Cell Infiltration after Anti-VEGF Therapy in Preclinical Mouse Models of Breast Cancer
The effect of blocking VEGF activity in solid tumors extends beyond inhibition of angiogenesis. However, no studies have compared the effectiveness of mechanistically different anti-VEGF inhibitors with respect to changes in tumor growth and alterations in the tumor microenvironment. In this study we use three distinct breast cancer models, a MDA-MB-231 xenograft model, a 4T1 syngenic model, and a transgenic model using MMTV-PyMT mice, to explore the effects of various anti-VEGF therapies on tumor vasculature, immune cell infiltration, and cytokine levels. Tumor vasculature and immune cell infiltration were evaluated using immunohistochemistry. Cytokine levels were evaluated using ELISA and electrochemiluminescence. We found that blocking the activation of VEGF receptor resulted in changes in intra-tumoral cytokine levels, specifically IL-1β, IL-6 and CXCL1. Modulation of the level these cytokines is important for controlling immune cell infiltration and ultimately tumor growth. Furthermore, we demonstrate that selective inhibition of VEGF binding to VEGFR2 with r84 is more effective at controlling tumor growth and inhibiting the infiltration of suppressive immune cells (MDSC, Treg, macrophages) while increasing the mature dendritic cell fraction than other anti-VEGF strategies. In addition, we found that changes in serum IL-1β and IL-6 levels correlated with response to therapy, identifying two possible biomarkers for assessing the effectiveness of anti-VEGF therapy in breast cancer patients
Unbiased Selection of Peptide–Peptoid Hybrids Specific for Lung Cancer Compared to Normal Lung Epithelial Cells
Unbiased Selection of Peptide–Peptoid Hybrids Specific for Lung Cancer Compared to Normal Lung Epithelial Cells
To
develop widely applicable diagnostic and potentially therapeutic
approaches overcoming protein heterogeneity in human cancer, we have
developed a technology to unbiasedly select high specificity compound(s)
that bind any biomolecule (e.g., proteins, lipids, carbohydrates)
presented on the cancer cell surface but not on normal cells. We utilized
a peptidomimetic based on-bead two-color (OBTC) combinatorial cell
screen that can detect differences between two cell surfaces at high
accuracy by looking for beads (where each bead in the library had
one peptide–peptoid hybrid on the surface) that only bound
cancer but not normal cells. We screened a library of 393 216
compounds targeting HCC4017 lung adenocarcinoma cells (labeled in
red) in the presence of HBEC30KT normal bronchial epithelial cells
(labeled in green) derived from the same tissue of the same patient.
This screen identified a peptide–peptoid hybrid called PPS1
which displayed high specific binding for HCC4017 cancer cells over
HBEC30KT cells. Specificity was validated through on-bead, ELISA-like
and magnetic bead pulldown studies, while a scrambled version of PPS1
did not show any binding. Of interest, the simple dimeric version
(PPS1D1) displayed cytotoxic activity on HCC4017 cells, but not on
normal HBEC30KT cells. PPS1D1 also strongly accumulated in HCC4017
lung cancer xenografts in mice over control constructs. We conclude
that such combinatorial screens using tumor and normal cells from
the same patient have significant potential to develop new reagents
for cancer biology, diagnosis, and potentially therapy