Combined Vascular Endothelial Growth Factor Receptor/Epidermal Growth Factor Receptor Blockade with Chemotherapy for Treatment of Local, Uterine, and Metastatic Soft Tissue Sarcoma

Abstract

Purpose: Soft tissue sarcoma (STS) is a rare heterogeneous malignancy. Overall survival has been stagnant for decades, primarily because systemic therapies are ineffective versus metastases, the leading cause of STS lethality. Consequently, we examined whether tyrosine kinase receptors active in STS growth signaling might be blockable and whether multireceptor blockade might synergize with low-dose STS chemotherapy by therapeutically affecting STS cells and their associated microenvironment. Experimental Design: Vandetanib (AstraZenca), a tyrosine kinase inhibitor of vascular endothelial growth factor receptor 2 and epidermal growth factor receptor, was evaluated alone and with chemotherapy in vitro and in vivo in three human STS nude mouse xenograft models of different STS locations (muscle, uterus, lung), stages (primary, metastatic), and subtypes (leiomyosarcoma, fibrosarcoma, uterine sarcoma: luciferase-expressing MES-SA human uterine sarcoma cells surgically implanted into uterine muscularis with bioluminescence tumor growth assessment; developed by us). Results: In vitro, human STS cells were sensitive to vandetanib. Vandetanib alone and with chemotherapy statistically significantly inhibited leiomyosarcoma local growth and fibrosarcoma lung metastasis. Direct injection of MES-SA into nude mice uterine muscularis resulted in high tumor take (88%), whereas s.c. injection resulted in no growth, suggesting microenvironmental tumor growth modulation. Vandetanib alone and with chemotherapy statistically significantly inhibited uterine sarcoma growth. In all models, vandetanib induced increased apoptosis, decreased tumor cell proliferation, and decreased angiogenesis. Conclusions: Vandetanib has antitumor effects against human STS subtypes in vitro and in vivo, where it also affects the tumor-associated microenvironment. Given the urgent need for better systemic approaches to STS, clinical trials evaluating vandetanib, perhaps with low-dose chemotherapy, seem warranted.Available soft tissue sarcoma (STS) chemotherapies have modest response rates with significant toxicities (1). Consequently, new STS therapies must be developed to improve the current STS 5-year survival rates of <50%. However, new STS treatment development and trials validation are hampered by their rarity and remarkable clinical heterogeneity. More than 50 separate STS histologic subtypes are recognized; these possess markedly diverse clinical courses and outcomes, perhaps reflecting the complex and variable array of molecular derangements underlying these STS biological distinctions (2). In the era of targeted therapeutics, exploiting any relevant unifying molecular abnormalities as might exist in STS has appeal. Analogous to solid malignancies, STS consist of both tumor and tumor-associated normal cells; STS growth, migration, and dissemination depend on cross-talk between these two compartments. STS are generally highly vascular and angiogenic, resulting in increased metastatic potential (3). Amidst diversity, these common STS proper...

Combining PCI-24781, a Novel Histone Deacetylase Inhibitor, with Chemotherapy for the Treatment of Soft Tissue Sarcoma

“…Animals received humane care as per the Animal Welfare Act and the NIH "Guide for the Care and Use of Laboratory Animals." Animal models were utilized as previously described (15). Trypan blue staining confirmed viable STS cells (SKLMS1 or HT1080 cells 1 × 10 6 /0.1 mL HBSS/mouse) were injected into the flank (SKLMS1 i.m., HT1080 s.c.) of 6-wk-old female SCID mice (n = 40/experiment), growth was measured twice weekly; HT1080GL cells (stably expressing green fluorescent protein/Luciferase) were tail vein injected, resulting in experimental lung metastases that could be followed by bioluminescence.…”

“…Immunohistochemistry and TUNEL assay were done as previously described (15). Staining distribution (% positive stained tumor cells) and intensity (0 = no staining, 1 = low, 2 = high) as well as CD31 counts (in 10× high-power fields) were evaluated and scored by three independent reviewers (GL, WR, and AL).…”

Establishment and characterization of a novel orthotopic mouse model for human uterine sarcoma with different metastatic potentials

“…Subcutaneous transplantation of MES-SA cells into nude mice has been performed in several studies [8][9][10][11]. However, no pulmonary metastases were observed in these ectopic transplantations of MES-SA cells.…”

“…Subcutaneously injected MES-SA cells in nude mice develop into tumors that maintain histological features nearly identical to those of the primary human uterine sarcoma. However, no metastatic potential has been observed in an orthotopic model using MES-SA cells [8][9][10][11]. …”

Dual inhibition of EGFR at protein and activity level via combinatorial blocking of PI4KIIα as anti-tumor strategy

“…To overcome these drawbacks, combinatorial treatment involving multiple targets is an absolute imperative (Koppikar et al, 2008; Ren et al, 2008; Martelli et al, 2012). In this study, we found that PI4KIIα could be an ideal combinatorial target for EGFR treatment via regulating EGFR degradation.…”