Author of

• 10557

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  P1.05 - Poster Session 1 - Preclinical Models of Therapeutics/Imaging (ID 156)

  • Event: WCLC 2013
  • Type: Poster Session
  • Track: Biology
  • Presentations: 1
  • Moderators:
  • Coordinates: 10/28/2013, 09:30 - 16:30, Exhibit Hall, Ground Level

  • 10562

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    P1.05-005 - VEGF signaling inhibition by cediranib enhances the antitumor and anti-metastatic effects of radiation therapy more substantially than chemotherapy in orthotopic lung cancer models (ID 1443)

    09:30 - 09:30  |  Author(s): P.D. Smith
    • Abstract

    Background
    The outcome for lung cancer patients remains poor and new therapeutic approaches are urgently needed. Cediranib is an orally available inhibitor of all 3 VEGFR tyrosine kinases. We evaluated the therapeutic efficacy and radiosensitizing effects of cediranib and paclitaxel, alone or in combination, in orthotopic models of human lung adenocarcinoma that mimic clinical patterns of malignant progression.

    Methods
    PC14PE6 or NCI-H441 human lung adenocarcinoma cells (1 x 10[6]) were injected into the left lungs of nude mice. Mice were randomized (8/group) to treatment with vehicle control, cediranib (3 mg/kg/day po), paclitaxel (200 µg/week ip), radiation to the left lung and mediastinum (20 Gy in 5 fractions over 2 weeks), or radiation with cediranib and/or paclitaxel. When controls became moribund, all mice were sacrificed and assessed for lung tumor burden and mediastinal nodal metastasis. Lung tumors and adjacent tissues were analyzed immunohistochemically.

    Results
    All treatments were well tolerated without significant differences in body weight between groups. In both models, cediranib or radiation therapy alone inhibited tumor growth and lymph node metastasis with efficacy superior to paclitaxel. Cediranib markedly enhanced the antitumor and antimetastatic effects of radiation with 99.3% and 92.1% reductions in primary lung tumor volume in the PC14PE6 and NCI-H441 models, respectively, while paclitaxel only modestly improved the effects of radiation therapy. Trimodality therapy resulted in a near-complete suppression of tumor growth and metastasis, with 99.8% and 98.3% reductions in tumor volume compared to control in the PC14PE6 and NCI-H441 models, respectively, without evidence of lymph node metastasis. Immunohistochemical analyses of lung tumors revealed that cediranib inhibited angiogenesis and tumor cell proliferation and increased tumor and endothelial cell apoptosis. The antiangiogenic and apoptotic effects of cediranib were substantially enhanced when combined with radiation and paclitaxel. Cediranib alone or in combination with radiation and/or paclitaxel increased VEGFR2 expression, but VEGF expression was not significantly impacted by treatment. VEGFR2/3 activation was blocked by cediranib alone or in combination therapy.

    	PC14PE6			NCI-H441
    Treatment	Left Lung Weight (mg)	Left Lung Tumor Volume (mm[3])	Mediastinal Lymph Node Metastasis	Left Lung Weight (mg)	Left Lung Tumor Volume (mm[3])	Mediastinal Lymph Node Metastasis
    Vehicle	710 (490-1210)	753 (254-1089)	7/8	935 (800-1230)	1146 (860-1601)	8/8
    Paclitaxel 200ug/week	545 (150-860)	506 (37-817)	6/8	785 (485-820)	820 (576-1208)	7/8
    Radiation 20Gy/5fractions	220** (50-360)	154* (34-270)	4/8	485** (330-820)	501* (333-879)	6/8
    Cediranib 3mg/kg/day	215* (70-540)	137* (13-316)	4/8	395** (230-570)	414** (261-698)	5/8
    Radiation +Paclitaxel	185** (60-260)	87** (21-268)	2/8	360** (260-650)	327** (236-651)	5/8
    Cediranib + Paclitaxel	125** (60-260)	41** (0-150)	1/8[†]	225** (160-630)	241** (79-651)	4/8[†]
    Radiation + Cediranib	50* (40-60)	0** (0-28)	0/8[†]	120** (70-190)	88** (1-182)	2/8[†]
    Radiation + Cediranib + Paclitaxel	40** (40-60)	0** (0-1)	0/8[†]	100** (60-120)	9** (1-64)	0/8[†]
    Data are presented as medians and ranges or as incidence. [†]p<0.05 versus vehicle (lymph nodes), *p<0.01, **p<0.001 versus vehicle (others)

    Conclusion
    Trimodality therapy with cediranib, paclitaxel, and radiation resulted in the near complete suppression of lung tumor growth and metastasis with markedly enhanced antiangiogenic and apoptotic effects. The radiosensitizing effects of cediranib upon lung tumors and their vasculature was superior to those of paclitaxel with markedly enhanced apoptosis. The combination of cediranib with radiotherapy or chemoradiotherapy is a potentially promising therapy for cancer and our data provides a strong basis for the design of clinical trials in lung adenocarcinoma patients.