The evasive promise of antiangiogenic therapy☆
Article Outline
Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis. Ebos JM, Lee CR, Cruz-Munoz W, Bjarnason GA, Christensen JG, Kerbel RS.
Herein we report that the VEGFR/PDGFR kinase inhibitor sunitinib/SU11248 can accelerate metastatic tumor growth and decrease overall survival in mice receiving short-term therapy in various metastasis assays, including after intravenous injection of tumor cells or after removal of primary orthotopically grown tumors. Acceleration of metastasis was also observed in mice receiving sunitinib prior to intravenous implantation of tumor cells, suggesting possible “metastatic conditioning” in multiple organs. Similar findings with additional VEGF receptor tyrosine kinase inhibitors implicate a class-specific effect for such agents. Importantly, these observations of metastatic acceleration were in contrast to the demonstrable antitumor benefits obtained when the same human breast cancer cells, as well as mouse or human melanoma cells, were grown orthotopically as primary tumors and subjected to identical sunitinib treatments.
[Abstract reproduced by permission of Cancer Cell 2009;15:232–239]
Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Pàez-Ribes M, Allen E, Hudock J, Takeda T, Okuyama H, Viñals F, Inoue M, Bergers G, Hanahan D, Casanovas O.
Multiple angiogenesis inhibitors have been therapeutically validated in preclinical cancer models, and several in clinical trials. Here we report that angiogenesis inhibitors targeting the VEGF pathway demonstrate antitumor effects in mouse models of pancreatic neuroendocrine carcinoma and glioblastoma but concomitantly elicit tumor adaptation and progression to stages of greater malignancy, with heightened invasiveness and in some cases increased lymphatic and distant metastasis. Increased invasiveness is also seen by genetic ablation of the Vegf-A gene in both models, substantiating the results of the pharmacological inhibitors. The realization that potent angiogenesis inhibition can alter the natural history of tumors by increasing invasion and metastasis warrants clinical investigation, as the prospect has important implications for the development of enduring antiangiogenic therapies.
[Abstract reproduced by permission of Cancer Cell 2009;15:220–231]
The rationale is – was ? – attractive: hepatocellular carcinoma (HCC), which is poorly responsive to conventional chemotherapy, can be controlled by drugs that disable overactive angiogenic signaling pathways [1]. Several drugs that affect angiogenic factors and growth factor signaling have appeared in the clinical setting in recent years. Sorafenib, not only blocks raf kinase, which is frequently active in HCC tumor cells, but also the kinase activity of VEGF and PDGF receptors which affect the proliferation of the supportive cells forming the tumor vasculature [2]. Two well-designed clinical trials showed that sorafenib significantly increases the survival of patients suffering from HCC [3], [4]. This breakthrough established sorafenib as the standard of care for patients with advanced HCC and launched a new era in the treatment of HCC. However, we should not have our expectations raised unduly: in terms of absolute number of month gain, the prolongation of survival is modest, the benefit is limited to selected patients (Child A, BCLC C) and some patients discontinue the treatment due to side effects. Now, two experimental investigations have drawn our attention to subtle, but no less insidious effects of these drugs.
Ebos et al. tested short-term therapy with either sunitinib or sorafenib on tumor burden [5]. They injected human metastatic breast cancer 231/LM2-4LUC+ cells expressing luciferase into the tail vein of SCID mice and assessed tumor burden by bioluminescence. In contrast to conventional radiology, this assay measures the mass of living cells and not tumor size. They observed that mice receiving sunitinib for a short period of 7
days either before or after injection of tumor cells suffered from an accelerated tumor growth resulting in a shorter survival. The same was observed in nu/nu mice treated with sorafenib or SU10944 and with human MeWo melanomas cells. In an adjuvant setting, mice treated for 7days just after resection of an orthotopic implanted tumor also suffered from an accelerated tumor growth and shorter survival. The increased overall tumor burden corresponded to a diffuse metastatic process in multiple organs. This short-term effect of VEGF receptor tyrosine kinase inhibition was in contrast to sustained sunitinib treatment of pre-established tumors which led, as expected, to significant growth inhibition of the primary tumor. The authors propose that short antiangiogenic therapy results in metastatic conditioning effect. This conditioning could be due to up-regulation of circulating pro-angiogenic growth factors or recruitment of endothelial progenitor cells which together may create a more favorable metastatic milieu. None of these possibilities have been experimentally tested. Surprisingly, even the levels of circulating VEGF have not been determined. Whatever the mechanism(s) at play, these results raise important issues regarding HCC therapy. Sorafenib is not always well tolerated and, not infrequently, patients have to interrupt its administration. Whether such interruptions favor progression of HCC is presently unknown, but needs to be taken into account and a second-line therapy within a protocol considered. Concerning the combination of systemic antiangiogenic therapy with TACE, an interrupted scheme with drug holidays during the TACE sessions has been contemplated [6], but seems, in light of these experimental data, rather contra-productive. Finally, whether interruption at the time of transplantation, of targeted therapy administered to patients awaiting transplant, exerts a negative impact on recurrence and countermands the benefits can only be addressed in adequately designed studies.
In a companion paper, Paez-Ribes tested the effect of antiangiogenic therapy on tumor invasiveness using the RIP1-Tag2 model of pancreatic neuroendocrine cancer [7]. They found that the tumor front of invasion is more frequently intermingled with the surrounding tissue without encapsulation already after 7days of treatment with an antibody against VEGF receptor-2. This effect was accentuated with longer therapy and persisted after cessation of the treatment. Using an elegant genetic manipulation of their model, the authors could document increased invasiveness and distant metastasis in tumor carrying a tumor cell-specific deletion of the Vegf-A gene. Treatment with the multi-kinase inhibitor, sunitinib produced a significant survival benefit, but in the end, induced a more aggressive tumor phenotype as demonstrated by widespread tumor infiltration, and hematogenic dissemination of tumor cell clusters far from the primary tumor. This was associated with hypoxia in the primary tumor. These findings were recapitulated in a second cancer model (orthotopic glioblastoma). These data show that antiangiogenic therapy elicits malignant progression by changing the tumor ecosystem. Abrogation of VEGF signaling results, after a period of transitory response characterized by hypoxia, in a resistance reaction that comprises activation of an invasive growth program, stimulation of back-up angiogenic pathways and emergence of resistant cells. The authors call this evasive resistance to antiangiogenic therapy. As in the paper of Ebos et al., this paper raises important issues regarding HCC therapy. The larger effect of sorafenib on the time to progression (about 100%) than on the survival (about 50%) suggests that such a selection process for a more aggressive phenotype may occur clinically. Several strategies to address this might be envisaged. One is to combine antiangiogenic drugs with conventional chemotherapy. Another one, more theoretical at this point, is to maintain a tolerable tumor volume to keep the tumor phenotype less aggressive and have, in fine, a higher impact on patient survival than to try to eradicate tumor cells with drugs which increase tumor hypoxia and push to aggressive tumor phenotype. Such a maintenance therapy has been mathematically analyzed and tested successfully in one experimental model [8]. The answer may also rely on the development of sophisticated biomarkers to tailor the therapy to the phenotype of the tumor.
Even if performed in non-HCC animal models, these investigations point to clinically relevant drug-induced changes in tumor biology. Antiangiogenic therapy for HCC is promising, but, as demonstrated by these two papers, has to be used judiciously in order to fulfil its promises.
References
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- Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell. 2009;15:220–231
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☆ The author declared that he does not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.
PII: S0168-8278(09)00466-8
doi:10.1016/j.jhep.2009.07.006
© 2009 European Association for the Study of the Liver. Published by Elsevier Inc. All rights reserved.
