Per Borgström

Neutralizing anti‐vascular endothelial growth factor antibody completely inhibits angiogenesis and growth of human prostate carcinoma micro tumors in vivo

Neovascularization mediated by growth factors produced by tumors is critical for the growth of tumors. Vascular endothelial growth factor (VEGF) is one such growth factor. A neutralizing anti‐VEGF antibody (A4.6.1) was recently shown in vivo to inhibit tumor angiogenesis and growth of the human rhabdomyosarcoma cell line A673. The antibody profoundly changed the growth characteristics of the tumor line from a rapidly growing malignancy to a dormant microcolony.

Vaccination with dendritic cells pulsed with apoptotic tumors in combination with anti-OX40 and anti-4-1BB monoclonal antibodies induces T cell-mediated protective immunity in Her-2/neu transgenic mice.

Tumor cells express tumor‐associated antigens (TAAs), which can serve as targets for the immune system. However, the majority of TAAs are overexpressed products of normal cellular genes; as such, self‐tolerance mechanisms have hindered their use for the induction of effective antitumor responses. One such normal self‐protein is the growth factor receptor Her‐2/neu, which is overexpressed in 25–35% of all mammary carcinomas in humans. In previous studies, we have demonstrated that Her‐2/neu mice are functionally tolerant to neu antigens and contain only a low avidity T‐cell repertoire to neu antigens. However, this residual low‐avidity T‐cell repertoire has antitumor activity. In this study, we compared the immune responses of Her‐2/neu mice immunized with dendritic cells (DCs) pulsed with soluble neu protein or with apoptotic tumor cells. Analysis of the antitumor response shows that Her‐2/neu mice vaccinated with DCs pulsed with Her‐2/neu antigens retard tumor growth; however, vaccination with DCs pulsed with apoptotic tumor cells induces a stronger antitumor effect. Administration of multiple immunizations in combination with the costimulatory agonist anti‐OX40 or anti‐4‐1BB MAb significantly enhanced the immune responses in these mice, resulting in complete tumor rejection if the tumor burden was small and substantial tumor reduction with a larger tumor burden. These results have important implications for the design of tumor vaccination strategies, suggesting that the use of vaccines that stimulate a broad immune response in combination with costimulatory molecules as immunomodulators could significantly improve the antitumor immune response in tolerant hosts.

Regression of prostate tumors upon combination of hormone ablation therapy and celecoxib in vivo

Hormonal ablation is the standard of treatment for advanced androgen‐dependent prostate cancer. Although tumor regression is usually achieved at first, the cancer inevitably evolves toward androgen‐independence, in part because of the development of mechanisms of resistance and in part because at the tissue level androgen withdrawal is not fully attained. Current research efforts are focused on new therapeutic strategies that will increase the effectiveness of androgen withdrawal and delay recurrence. We used a syngeneic pseudo‐orthotropic mouse model of prostate cancer to test the efficacy of combining androgen withdrawal with FDA‐approved COX‐2 inhibitor celecoxib.

The combination of plumbagin with androgen withdrawal causes profound regression of prostate tumors in vivo

Hormonal ablation is the standard treatment for disseminated androgen‐dependent prostate cancer. Although tumor growth is controlled at first, the tumor invariably recurs in the form of castration‐resistant prostate cancer. This study assessed the efficacy of a new therapeutic strategy that combines plumbagin, a naturally occurring naphthoquinone, with androgen ablation.

Effects of Different Tissue Microenvironments on Gene Expression in Breast Cancer Cells

In metastasis, circulating tumor cells penetrate the walls of blood vessels and enter the metastatic target tissue, thereby becoming exposed to novel and relatively unsupportive microenvironments. In the new microenvironments, the tumor cells often remain in a dormant state indefinitely and must adapt before they are able to successfully colonize the tissue. Very little is known about this adaptive process. We studied temporal changes in gene expression when breast cancer cells adapt to survive and grow on brain, bone marrow, and lung tissue maintained in an in vivo culture system, as models of the metastatic colonization of these tissues. We observed the transient activation of genes typically associated with homeostasis and stress during the initial stages of adaptation, followed by the activation of genes that mediate more advanced functions, such as elaboration of cell morphology and cell division, as the cells adapted to thrive in the host tissue microenvironment. We also observed the temporary induction of genes characteristic of the host tissue, which was particularly evident when tumor cells were grown on brain tissue. These early transient gene expression events suggest potential points of therapeutic intervention that are not evident in data from well-established tumors.

A Selective Tumor Microvasculature Thrombogen that Targets a Novel Receptor Complex in the Tumor Angiogenic Microenvironment

We have previously shown that part of the heparin-binding domain of the vascular endothelial growth factor (VEGF), designated HBDt, localizes very selectively to surfaces of the endothelial cells of i.t blood vessels. Here, we have coupled the HBDt to the extracellular domain of tissue factor (TFt), to locally initiate the thrombogenic cascade. In tumor-bearing mice, infusion of this HBDt.TFt results in rapid occlusive thrombosis selective only for tumor microvasculature with resultant infarctive destruction of tumors. We now show that infusion of an optimal combination of this HBDt.TFt and its requisite cofactor (factor VIIa) in tumor models results in significant tumor eradication. Binding studies and confocal microscopy indicate that the target for the HBDt.TFt seems to be a trimolecular complex of chondroitin C sulfate proteoglycan, neuropilin-1, and VEGF receptor-2, overexpressed together only in highly angiogenic sites of the tumor microenvironment. The HBDt.TFt was also colocalized with the trimolecular receptor complex in endothelial sprouts from tumor tissues, and its binding inhibited the growth of such sprouts. In vitro, we show that the HBDt structure has its highest affinity for chondroitin 6 sulfate. We show the potential of this HBDt.TFt as a candidate therapeutic and elucidate its target in vivo.

Abstract 3244: Combination of COX-2 inhibitor Celebrex with androgen deprivation synergistically inhibits tumor growth in a syngeneic mouse model of prostate cancer

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Prostate cancer (PC) is the most common solid tumor in men in the United States. Effective treatment options include surgery and radiation therapy for localized tumors, whereas advanced cancer is treated by androgen deprivation. Unfortunately, most patients with metastatic prostate cancer will eventually relapse into a hormone-independent cancer that is notoriously resistant to chemotherapy. Thus, more effective therapeutic strategies are needed to improve this outcome, which leads to about 30 000 deaths every year. Nonsteroidal anti-inflammatory drugs (NSAIDs) have shown efficacy for the prevention or the treatment of several human cancers. Among them, specific COX-2 inhibitors have received particular attention because COX-2 is overexpressed in many epithelial tumors, including prostate, and because a number of studies have shown that they slow the growth of colon, lung and breast tumor xenografts in mice. In addition, COX-2 inhibitors have potent antitumor activity in prostate cancer both in vitro and in vivo. Celebrex (Celecoxib), the only COX-2 inhibitor still approved for clinical use, is being evaluated in clinical trials for the treatment of localized or advanced prostate cancer. In this study, we observed that celebrex in combination with androgen deprivation inhibits tumor growth much more efficiently that either treatment alone. A syngeneic pseudo-orthotropic mouse model and Intravital Microscopy (IVM) were used to measure several parameters of tumor progression and study the effect of Celebrex combined with androgen deprivation. Androgen-dependent TRAMP-C2 mouse prostate cancer cells were co-implanted with prostate tissue into the dorsal skinfold chamber of syngeneic C57Bl/6 mice. Mice were subjected to surgical or hormonal castration, alone or in combination with Celebrex. Tumor growth, apoptosis, mitosis and angiogenesis were measured. We observed that Celebrex alone inhibited tumor growth with no evidence of apoptosis but most likely through growth arrest during mitosis. Interestingly, Celebrex alone had no effect on angiogenesis. Castration alone had a significant angiostatic effect but tumor growth was inhibited only by 20%. In contrast, the combination of castration and Celebrex inhibited tumor growth by 65% and resulted in both increased apoptosis and increased mitotic arrest. Conclusion: our study provides evidence that Celebrex treatment of prostate cancer-bearing mice results in a lower proliferative rate in tumors. In addition, Celebrex potentiates the effect of castration to inhibit tumor growth in vivo. We propose therefore that administration of Celebrex during androgen deprivation may be more efficient than androgen deprivation alone and warrants further study. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3244.