Phase Ib trial of radiotherapy in combination with combretastatin-A4-phosphate in patients with non-small-cell lung cancer, prostate adenocarcinoma, and squamous cell carcinoma of the head and neck

Ng, Q.S.; Mandeville, Henry; Goh, Vicky; Alonzi, R.; Milner, Jessica; Carnell, Dawn; Meer, Khalda; Padhani, Anwar R.; Saunders, M.I.; Hoskin, Peter

doi:10.1093/annonc/mdr332

Cited by 63 publications

(40 citation statements)

References 21 publications

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“…With the aim to complement CA4P treatment, 131 I-Hyp is intravenously administrated 24 hours after the CA4P dose to eliminate the remaining cancer cells and to prevent tumor regrowth (Fig. 1,3,4) 42,87,88. The engineered design for SMSDTTS that combines sequential intravenous injection of CA4P and 131 I-Hyp at a 24h interval is believed advantageous for the following considerations: a) being both naturally derived small molecules allowing systemic injections with much better accessibility to targeted tissues, CA4P and Hyp (in the form of its radiolabeled iodo-derivative) share a highly targeting capacity but diverse and complementary specificities; b) massive intra-tumoral necrosis induced by CA4P serves as a target or anchor for 131 I-Hyp; c) a 24h interval between CA4P and 131 I-Hyp allows the complete formation of necrosis, meanwhile optimal accessibility to the latter due to partial recovery of tumor vascularization 89; d) iodine-131 that emits tumoricidal beta particles and gamma rays useful for scintigraphy provides a theragnostic solution for malignancies; e) being spatially or geographically cooperational, CA4P kills tumor cells inside out, whereas 131 I-Hyp eradicates the remnant tumor cells on the periphery.…”

Section: Engineered Designs With Smsdttsmentioning

confidence: 99%

Small Molecule Sequential Dual-Targeting Theragnostic Strategy (SMSDTTS): from Preclinical Experiments towards Possible Clinical Anticancer Applications

Li¹,

Oyen²,

Verbruggen³

et al. 2013

J. Cancer

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Hitting the evasive tumor cells proves challenging in targeted cancer therapies. A general and unconventional anticancer approach namely small molecule sequential dual-targeting theragnostic strategy (SMSDTTS) has recently been introduced with the aims to target and debulk the tumor mass, wipe out the residual tumor cells, and meanwhile enable cancer detectability. This dual targeting approach works in two steps for systemic delivery of two naturally derived drugs. First, an anti-tubulin vascular disrupting agent, e.g., combretastatin A4 phosphate (CA4P), is injected to selectively cut off tumor blood supply and to cause massive necrosis, which nevertheless always leaves peripheral tumor residues. Secondly, a necrosis-avid radiopharmaceutical, namely 131I-hypericin (131I-Hyp), is administered the next day, which accumulates in intratumoral necrosis and irradiates the residual cancer cells with beta particles. Theoretically, this complementary targeted approach may biologically and radioactively ablate solid tumors and reduce the risk of local recurrence, remote metastases, and thus cancer mortality. Meanwhile, the emitted gamma rays facilitate radio-scintigraphy to detect tumors and follow up the therapy, hence a simultaneous theragnostic approach. SMSDTTS has now shown promise from multicenter animal experiments and may demonstrate unique anticancer efficacy in upcoming preliminary clinical trials. In this short review article, information about the two involved agents, the rationale of SMSDTTS, its preclinical antitumor efficacy, multifocal targetability, simultaneous theragnostic property, and toxicities of the dose regimens are summarized. Meanwhile, possible drawbacks, practical challenges and future improvement with SMSDTTS are discussed, which hopefully may help to push forward this strategy from preclinical experiments towards possible clinical applications.

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Section: Engineered Designs With Smsdttsmentioning

confidence: 99%

Small Molecule Sequential Dual-Targeting Theragnostic Strategy (SMSDTTS): from Preclinical Experiments towards Possible Clinical Anticancer Applications

Li¹,

Oyen²,

Verbruggen³

et al. 2013

J. Cancer

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“…Thus, effective use of such vascular disrupting agents will require combination with additional conventional therapeutic approaches and several studies have demonstrated enhanced tumor response by combination with irradiation or chemotherapeutic agents [6, 7]. Combretastatin A-4 phosphate (CA4P; fosbretabulin), a tubulin-depolymerizing agent structurally related to colchicine, has been shown to cause vascular disruption and is subject to ongoing clinical trials [2, 8–10]. …”

Section: Introductionmentioning

confidence: 99%

Dynamic bioluminescence and fluorescence imaging of the effects of the antivascular agent Combretastatin-A4P (CA4P) on brain tumor xenografts

2015

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Combretastatin A-4 (CA4) is a natural product isolated from Combretum caffrum that inhibits tubulin polymerization by binding to the colchicine-binding site. A corresponding water soluble pro-drug (referred to as CA4P), has undergone extensive clinical trials and has been evaluated in pre-clinical studies using multiple modalities. We previously reported a novel assay based on dynamic bioluminescent imaging to assess tumor vascular disruption and now present its application to assessing multiple tumors simultaneously. The current study evaluated the vascular-disrupting activity of CA4P on subcutaneous 9L rat brain tumor xenografts in mice using dynamic bioluminescence imaging. A single dose of CA4P (120 mg/kg, intraperitoneally) induced rapid, temporary tumor vascular shutdown revealed by a rapid and reproducible decrease of light emission from luciferase-expressing 9L tumors following administration of luciferin as a substrate. A time-dependent reduction of tumor perfusion after CA4P treatment was confirmed by immunohistological assessment of the perfusion marker Hoechst 33342 and the tumor vasculature marker CD31. The vasculature showed distinct recovery within 24 hours post therapy. Multiple tumors behaved similarly, although a size dependent vascular inhibition was observed. In conclusion, CA4P caused rapid, temporary tumor vascular shutdown and led to reduction of tumor perfusion in rat brain tumor xenografts and the multiple tumor approach should lead to more efficient studies requiring fewer animals and greater consistency.

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“…CA4P induces necrosis in central tumor cells but not peripheral tumor cells, which are nourished by blood from adjacent normal tissues and survive and repopulate rapidly (18). CA4P has been used with chemotherapy, radiotherapy, and/or hyperthermia against a range of tumor types in clinical trials (19, 20). The schedule, sequence, and timing of VDAs and combination therapies are crucial in determining the antitumor efficacy of the combination therapy because of VDAs’ prominent impact on tumor vasculature (21).…”

Section: Discussionmentioning

confidence: 99%

Hepatocellular Carcinoma: Intra-arterial Delivery of Doxorubicin-loaded Hollow Gold Nanospheres for Photothermal Ablation—Chemoembolization Therapy in Rats

Li¹,

Zhou²,

Liu³

et al. 2016

Radiology

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Purpose To determine if combretastatin A-4 phosphate disodium (CA4P) can enhance the tumor uptake of doxorubicin (Dox)-loaded, polyethylene glycol (PEG)-coated hollow gold nanospheres (HAuNS) mixed with Lipiodol (Dox@PEG-HAuNS/Lipiodol) for improved photothermal ablation (PTA)-chemoembolization therapy (CET; PTA-CET) of hepatocellular carcinoma (HCC) in rats. Materials and Methods All animal experiments were approved by the Institutional Animal Care and Use Committee, and were performed in 45 Sprague-Dawley rats (male, 12 weeks old) from Feb. 2014 to April 2015. Eight days after inoculation of N1S1 HCC cells in the liver of rats. Animals were randomly divided into 2 groups of 10 rats each. Rats in group 1 received intrahepatic arterial (IA) injection of PEG-HAuNS/Lipiodol alone, and rats in group 2 received IA injection of CA4P followed by PEG-HAuNS/Lipiodol 5 min later. Each group was subdivided, and the Au content of tumors and tissues excised at 1 h or at 24 h was quantified using neutron activation analysis (NAA, n=5/time point). Five rats received CA4P plus PEG-[64Cu]-HAuNS/Lipiodol and underwent μPET/CT. In a separate study, therapeutic effects were compared among 3 groups of 6 rats each that received IA injection of saline (control group), CA4P plus Dox@PEG-HAuNS/Lipiodol (CET group), or CA4P plus Dox@PEG-HAuNS/Lipiodol plus near-infrared irradiation (PTA-CET group). Temperature was recorded during laser irradiation. Findings were verified with postmortem histopathology and/or autoradiography. Wilcoxon rank-sum test was used to test the difference between groups, Pearson correlation analyses were performed to evaluate correlations. Results PEG-HAuNS uptake in CA4P-pretreated tumors was significantly higher than that in non–CA4P-pretreated tumors at both 1 h (P<0.03) and 24 h (P<0.01). The tumor-to-liver PEG-HAuNS uptake ratios at 1 h and 24 h were 5.63±3.09 and 1.68±0.77, respectively, in the CA4P-treated group and 1.29±2.40 and 0.14±0.11, respectively, in the non–CA4P-treated group. μPET/CT clearly delineated the tumors, enabling quantitative imaging analysis. Laser irradiation increases temperature to 60°C and 43°C in the tumor and adjacent liver, respectively. Tumor volumes 10 d after therapy were 1.68±1.01, 3.96±1.75, and 6.13±2.27 cm3 in the PTA-CET, CET, and control groups, respectively, with significant differences between the PTA-CET group and other groups (P<0.05). Conclusion CA4P pretreatment causes a higher concentration of Dox@PEG-HAuNS to be trapped inside the tumor, thereby enhancing the anti-HCC efficacy of PTA-CET in rats.

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Phase Ib trial of radiotherapy in combination with combretastatin-A4-phosphate in patients with non-small-cell lung cancer, prostate adenocarcinoma, and squamous cell carcinoma of the head and neck

Abstract: Radiotherapy with CA4P appears well tolerated in most patients. The combination of CA4P, cetuximab, and radiotherapy needs further scrutiny before it can be recommended for clinical studies.

Cited by 63 publications

References 21 publications

Small Molecule Sequential Dual-Targeting Theragnostic Strategy (SMSDTTS): from Preclinical Experiments towards Possible Clinical Anticancer Applications

Small Molecule Sequential Dual-Targeting Theragnostic Strategy (SMSDTTS): from Preclinical Experiments towards Possible Clinical Anticancer Applications

Dynamic bioluminescence and fluorescence imaging of the effects of the antivascular agent Combretastatin-A4P (CA4P) on brain tumor xenografts

Hepatocellular Carcinoma: Intra-arterial Delivery of Doxorubicin-loaded Hollow Gold Nanospheres for Photothermal Ablation—Chemoembolization Therapy in Rats

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