American Association for Cancer Research
10780432ccr150915-sup-147802_1_supp_3014291_npqrd7.docx (1.24 MB)

Supplemental figures 1-3 from Potential Proinvasive or Metastatic Effects of Preclinical Antiangiogenic Therapy Are Prevented by Concurrent Chemotherapy

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journal contribution
posted on 2023-03-31, 19:00 authored by Marta Paez-Ribes, Shan Man, Ping Xu, Robert S. Kerbel

Supplemental figures 1-3. Supplemental figure 1. Addition of chemotherapy enhances tumor growth inhibition and blocks local tumor invasion. Supplemental figure 2. Cyclophosphamide, when added to antiangiogenic therapy, inhibits tumor growth and blocks local tumor invasion. Supplemental figure 3. Reduced doses of DC101 had milder effects on local tumor invasion.



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 well—chemotherapy may improve the impact of antiangiogenic drug treatment and, as a result, overall efficacy. Clin Cancer Res; 21(24); 5488–98. ©2015 AACR.

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