A Model of Postsurgical Advanced Metastatic Breast Cancer More Accurately Replicates the Clinical Efficacy of Antiangiogenic Drugs

Guérin, Éric; Man, Shan; Xu, Ping; Kerbel, Robert S.

doi:10.1158/0008-5472.can-12-4183

Cited by 84 publications

(92 citation statements)

References 27 publications

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“…As we reported in previous studies, improved therapeutic outcomes, such as increase in survival or inhibition of tumor growth, observed in primary tumor studies, do not necessarily predict or correlate with the efficacy of the same drug or therapy in postsurgical metastatic studies (43,44). In this regard, the clinical analyses of the impact of antiangiogenic drugs have virtually all involved patients with early-or late-stage metastatic disease (34,35) We therefore assessed the impact of DC101 plus paclitaxel in an adjuvant treatment model, where therapy was started soon after primary tumors were resected.…”

Section: Impact Of Dc101 Combined With Chemotherapy In the Adjuvant Smentioning

confidence: 66%

Potential Proinvasive or Metastatic Effects of Preclinical Antiangiogenic Therapy Are Prevented by Concurrent Chemotherapy

Páez-Ribes

Man

et al. 2015

Clinical Cancer Research

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Purpose: To resolve a controversy involving the therapeutic impact of antiangiogenic drugs and particularly antibodies targeting the VEGF pathway, namely, a body of preclinical mouse therapy studies showing such drugs can promote invasion and/or distant metastasis when used as monotherapies. In contrast, clinical studies have not shown such promalignancy effects. However, most such clinical studies have involved patients also treated with concurrent chemotherapy highlighting the possibility that chemotherapy may prevent any potential promalignancy effect caused by an antiangiogenic drug treatment.Experimental Design: The impact of antiangiogenic therapy using DC101, an antibody targeting mouse VEGFR-2 with or without concurrent chemotherapy was assessed in multiple human breast cancer xenograft models, where impact on orthotopic primary tumors was evaluated. Metastasis was also assessed during adjuvant and neoadjuvant plus adjuvant therapy, after surgical resection of primary tumors, with the same combination therapies.Results: Antiangiogenic therapy, while blunting tumor volume growth, was found to increase local invasion in multiple primary tumor models, including a patient-derived xenograft, but this effect was blocked by concurrent chemotherapy. Similarly, the combination of paclitaxel with DC101 caused a marked reduction of micro-or macrometastatic disease in contrast to DC101 monotherapy, which was associated with small increases in metastatic disease.Conclusions: Conventional wisdom is that targeted biologic antiangiogenic agents such as bevacizumab when used with chemotherapy increase the efficacy of the chemotherapy treatment. Our results suggest the reverse may be true as wellchemotherapy may improve the impact of antiangiogenic drug treatment and, as a result, overall efficacy.

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Section: Impact Of Dc101 Combined With Chemotherapy In the Adjuvant Smentioning

confidence: 66%

Potential Proinvasive or Metastatic Effects of Preclinical Antiangiogenic Therapy Are Prevented by Concurrent Chemotherapy

Páez-Ribes

Man

et al. 2015

Clinical Cancer Research

Self Cite

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“…However, no survival benefit was seen in mice bearing spontaneous lung metastasis in which only a microscopic disease of either tumor type was observed in the lungs. Guerin and colleagues have recently shown that the antitumor activity of antiangiogenic drugs is effective in the treatment of primary tumors but was either ineffective or showed modest therapeutic benefit in a postsurgical advanced metastatic disease model (39). In addition, a recent study by Rovida and colleagues showed that the combination of various chemotherapy drugs, including doxorubicin, topotecan, and gemcitabine but not paclitaxel and cisplatin, inhibited the prometastatic effects of sunitinib (40).…”

Section: Discussionmentioning

confidence: 99%

Differential Therapeutic Effects of Anti–VEGF-A Antibody in Different Tumor Models: Implications for Choosing Appropriate Tumor Models for Drug Testing

Alishekevitz

Bril

Loven

et al. 2014

Molecular Cancer Therapeutics

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We previously reported that the host response to certain chemotherapies can induce primary tumor regrowth, angiogenesis, and even metastases in mice, but the possible impact of anti-VEGF-A therapy in this context has not been fully explored. We, therefore, used combinations of anti-VEGF-A with chemotherapy on various tumor models in mice, including primary tumors, experimental lung metastases, and spontaneous lung metastases of 4T1-breast and CT26-colon murine cancer cell lines. Our results show that a combined treatment with anti-VEGF-A and folinic acid/5-fluorouracil/oxaliplatin (FOLFOX) but not with anti-VEGF-A and gemcitabine/cisplatinum (Gem/CDDP) enhances the treatment outcome partly due to reduced angiogenesis, in both primary tumors and experimental lung metastases models. However, neither treatment group exhibited an improved treatment outcome in the spontaneous lung metastases model, nor were changes in endothelial cell numbers found at metastatic sites. As chemotherapy has recently been shown to induce tumor cell invasion, we tested the invasion properties of tumor cells when exposed to plasma from FOLFOX-treated mice or patients with cancer. While plasma from FOLFOX-treated mice or patients induced invasion properties of tumor cells, the combination of anti-VEGF-A and FOLFOX abrogated these effects, despite the reduced plasma VEGF-A levels detected in FOLFOX-treated mice. These results suggest that the therapeutic impact of antiangiogenic drugs varies in different tumor models, and that anti-VEGF-A therapy can block the invasion properties of tumor cells in response to chemotherapy. These results may implicate an additional therapeutic role for anti-VEGF-A when combined with chemotherapy. Mol Cancer Ther; 13(1); 202-13. Ó2013 AACR.

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“…The discrepancy between the effects of anti-cancer therapies on experimental tumor growth and the response to these drugs in metastatic patients enrolled in early clinical trials may explain why about 85% of new drugs fail [189]. Mouse models have revealed meaningful disparities between the response of primary tumors and their visceral metastases to anti-cancer therapies [190,191]. In this regard, choosing pre-clinical models that accurately represent each stage of the metastatic cascade is also critical to understand basic biological mechanisms of metastasis formation as it occurs in patients [192] and to specifically target metastatic disease (Figure 3).…”

Section: Discussionmentioning

confidence: 99%

Immune-mediated mechanisms influencing the efficacy of anticancer therapies

Coffelt

Visser

2015

Trends in Immunology

125

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SummaryConventional anti-cancer therapies, such as chemotherapy, radiotherapy and targeted therapy, are designed to kill cancer cells. Yet, the efficacy of anti-cancer therapies is not only determined by their direct effects on cancer cells, but also by off-target effects within the host immune system. Cytotoxic treatment regimens elicit a number of changes in immune-related parameters including the composition, phenotype and function of immune cells. In this review, we discuss the impact of innate and adaptive immune cells on the success of anti-cancer therapy, we examine the opportunities to exploit host immune responses to boost tumor clearing and we highlight the challenges facing the treatment of advanced metastatic disease. Then and now: The link between the immune system and anti-cancer therapiesThe relationship between anti-cancer therapies and the immune system is as old as the invention of anti-cancer therapies themselves. After the use of mustard gas in the trenches of World War I, a seminal observation was made that some exposed soldiers displayed severe loss of bone marrow and lymph node cells [1]. This observation then spurred the idea that the anti-proliferative capacity of mustard gas may also slow the growth of cancer cells.Experiments carried out in mice transplanted with lymphoid tumors were convincing enough to treat a lymphoma patient [2], and these events initiated the standardized treatment of cancer patients with chemotherapy [3,4].Fast forward 100 years later. The influence of immune cells on tumor progression and metastasis is well established [5], and an appreciation for the immune system's impact during conventional anti-cancer therapy treatment is growing. Recent seminal advances indicate that immune cells can shape the outcome of various anti-cancer therapies. As such, 2 immune cells and their molecular mediators have evolved into bona vide targets of therapeutic manipulation in cancer patients. The recent breakthrough of immunotherapeutics that inhibit negative immune regulatory pathways, such as anti-CTLA4 and anti-PD1, has initiated a new era in the treatment of cancer [6]. In parallel, immunomodulatory strategies aimed at dampening pro-tumor functions of immune cells are currently being tested in cancer patients [7]. Immune cells also function as reliable biomarkers, since their abundance or activation status often predicts how well patients respond to a particular treatment regimen.Here, we review these novel experimental and clinical insights, highlighting potential implications for the development of synergistic therapies designed to combat primary tumors and, more importantly, metastatic disease. The pros and cons of experimental mouse modelsResearch questions aimed at understanding the role of immune cells during anti-cancer therapy require models that mirror the complex interactions between the immune system and diverse forms of human cancers. Transplantable cancer cell line models and carcinogeninduced cancer models are the most frequently used for these purposes. However...

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A Model of Postsurgical Advanced Metastatic Breast Cancer More Accurately Replicates the Clinical Efficacy of Antiangiogenic Drugs

Cited by 84 publications

References 27 publications

Potential Proinvasive or Metastatic Effects of Preclinical Antiangiogenic Therapy Are Prevented by Concurrent Chemotherapy

Potential Proinvasive or Metastatic Effects of Preclinical Antiangiogenic Therapy Are Prevented by Concurrent Chemotherapy

Differential Therapeutic Effects of Anti–VEGF-A Antibody in Different Tumor Models: Implications for Choosing Appropriate Tumor Models for Drug Testing

Immune-mediated mechanisms influencing the efficacy of anticancer therapies

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