Toward Prediction of Efficacy of Chemotherapy: A Proof of Concept Study in Lung Cancer Patients Using [11C]docetaxel and Positron Emission Tomography

Veldt, Astrid A.M. van der; Lubberink, Mark; Mathijssen, Ron H.J.; Loos, Walter J.; Herder, Gerarda J.M.; Greuter, Henri N.; Comans, Emile F.I.; Rutten, Hugo B.; Eriksson, Jonas; Windhorst, Albert D.; Hendrikse, N. Harry; Postmus, Pieter E.; Smit, Egbert F.; Lammertsma, Adriaan A.

doi:10.1158/1078-0432.ccr-12-3779

Cited by 62 publications

(45 citation statements)

References 29 publications

(37 reference statements)

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“…A difficulty in performing such a study with DIPG patients is that current DIPG trials involve multiagent therapy regimens. The finding that bevacizumab can reduce the penetration of other drugs into tumors (22,23) underlines the need for labeled-drug imaging in this multiagent setting. On the other hand, in contrast to single-agent settings, multiagent therapy may confound the association of the imaging biomarker and outcome-so that clinical validation of this immuno-PET method as a predictive biomarker of the response to therapy requires larger datasets.…”

Section: Discussionmentioning

confidence: 99%

Molecular Drug Imaging: ⁸⁹Zr-Bevacizumab PET in Children with Diffuse Intrinsic Pontine Glioma

et al. 2016

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Predictive tools for guiding therapy in children with brain tumors are urgently needed. In this first molecular drug imaging study in children, we investigated whether bevacizumab can reach tumors in children with diffuse intrinsic pontine glioma (DIPG) by measuring the tumor uptake of 89 Zr-labeled bevacizumab by PET. In addition, we evaluated the safety of the procedure in children and determined the optimal time for imaging. Methods: Patients received 89 Zr-bevacizumab (0.1 mg/kg; 0.9 MBq/kg) at least 2 wk after completing radiotherapy. Whole-body PET/CT scans were obtained 1, 72, and 144 h after injection. All patients underwent contrast (gadolinium)-enhanced MRI. The biodistribution of 89 Zr-bevacizumab was quantified as SUVs. Results: Seven DIPG patients (4 boys; 6-17 y old) were scanned without anesthesia. No adverse events occurred. Five of 7 primary tumors showed focal 89 Zr-bevacizumab uptake (SUVs at 144 h after injection were 1.0-6.7), whereas no significant uptake was seen in the healthy brain. In 1 patient, multiple metastases all showed positive PET results. We observed inter-and intratumoral heterogeneity of uptake, and 89 Zr-bevacizumab uptake was present predominantly (in 4/5 patients) within MRI contrast-enhanced areas, although 89 Zr-bevacizumab uptake in these areas was variable. Tumor targeting results were quantitatively similar at 72 and 144 h after injection, but tumor-to-blood-pool SUV ratios increased with time after injection (P 5 0.045). The mean effective dose per patient was 0.9 mSv/MBq (SD, 0.3 mSv/MBq). Conclusion: 89 Zr-bevacizumab PET studies are feasible in children with DIPG. The data suggest considerable heterogeneity in drug delivery among patients and within DIPG tumors and a positive, but not 1:1, correlation between MRI contrast enhancement and 89 Zr-bevacizumab uptake. The optimal time for scanning is 144 h after injection. Tumor 89 Zr-bevacizumab accumulation assessed by PET scanning may help in the selection of patients with the greatest chance of benefit from bevacizumab treatment.

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Section: Discussionmentioning

confidence: 99%

Molecular Drug Imaging: ⁸⁹Zr-Bevacizumab PET in Children with Diffuse Intrinsic Pontine Glioma

et al. 2016

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“…For example, the relative uptake of doxorubicin in the tumor (expressed as percentage injected dose per gram, or %ID/g) was found to be only 5-10% of the corresponding values in lung, heart or liver, in the time period 0.5 -8 hours [5]. Importantly, similar trends are emerging from the positron emission tomography study of cancer patients, who had received radiolabeled preparations of cytotoxic drugs [3,4].…”

Section: Introductionmentioning

confidence: 94%

“…The majority of cytotoxic agents used for the pharmacotherapy of cancer do not preferentially accumulate at the tumor site, leading to potential toxicities and to suboptimal therapeutic efficacy [1][2][3][4]. In tumor-bearing mice, unfavorable tumor:organ ratios have been reported for many drugs, including doxorubicin [5], paclitaxel [6], cisplatin [7], cyclophosphamide [8], sunitinib [9], and different fluorinated pyrimidines [10], to name just a few.…”

Section: Introductionmentioning

confidence: 99%

Acetazolamide Serves as Selective Delivery Vehicle for Dipeptide-Linked Drugs to Renal Cell Carcinoma

Cazzamalli

Corso

Neri

2016

Molecular Cancer Therapeutics

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In most cases, cytotoxic drugs do not preferentially accumulate at the tumor site, causing unwanted toxicities and preventing dose escalation to therapeutically active regimens. Here, we show that acetazolamide derivatives, which bind to carbonic anhydrase IX (CAIX) on the surface of kidney cancer cells, selectively deliver payloads at the site of disease, sparing normal organs. Biodistribution studies, performed in tumor-bearing mice with acetazolamide derivatives bearing a technetium-99m chelator complex or a red fluorophore as payload, revealed a preferential tumor accumulation of the compound at doses up to 560 nmol/Kg. The percentage of injected dose per gram in the tumor was dose-dependent and revealed optimal tumor:organ ratios at 140 nmol/Kg, with a tumor:blood ratio of 80:1 at 6 h. Acetazolamide, coupled to potent cytotoxic drugs via a dipeptide linker, exhibited a potent antitumor activity in nude mice bearing SKRC-52 renal cell carcinomas, while drug derivatives devoid of the acetazolamide moiety did not exhibit any detectable anticancer activity at the same doses. The observation of tumor regression with a noninternalizing ligand and with different cytotoxic moieties (MMAE and PNU-159682) indicates a general mechanism of action, based on the selective accumulation of the product on tumor cells, followed by the extracellular proteolytic release of the cytotoxic payload at the neoplastic site and the subsequent drug internalization into tumor cells. Acetazolamide-based drug conjugates may represent a promising class of targeted agents for the treatment of metastatic kidney cancer, as the majority of human clear cell renal cell carcinomas are strongly positive for CAIX.

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“…11 C]DACA [119] , and [ 11 C]docetaxel [120,121] . Consequently, tumor perfusion may be predictive of tumor response to the above mentioned anticancer drugs.…”

Section: Tumor Perfusion and Drug Deliverymentioning

confidence: 99%

Positron emission tomography to assess hypoxia and perfusion in lung cancer

Verwer

Boellaard

Veldt

2014

WJCO

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Core tip:This review provides an overview of the current applications of positron emission tomography for hypoxia and perfusion imaging in lung cancer. Available PET tracers are discussed and the benefits of combined hypoxia and perfusion PET imaging are clarified. Hypoxia imaging could aid in selecting patients for hypoxia-specific treatment strategies. To achieve this, consensus about the optimal imaging protocol and quantification method is essential. Large clinical trials are needed to confirm the value of hypoxia imaging for improving patient care.Verwer EE, Boellaard R, van der Veldt AAM. Positron emission tomography to assess hypoxia and perfusion in lung cancer.

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Toward Prediction of Efficacy of Chemotherapy: A Proof of Concept Study in Lung Cancer Patients Using [11C]docetaxel and Positron Emission Tomography

Abstract: Purpose: Pharmacokinetics of docetaxel can be measured in vivo using positron emission tomography (PET) and a microdose of radiolabeled docetaxel ([ 11 C]docetaxel

Cited by 62 publications

References 29 publications

Molecular Drug Imaging: ⁸⁹Zr-Bevacizumab PET in Children with Diffuse Intrinsic Pontine Glioma

Molecular Drug Imaging: ⁸⁹Zr-Bevacizumab PET in Children with Diffuse Intrinsic Pontine Glioma

Acetazolamide Serves as Selective Delivery Vehicle for Dipeptide-Linked Drugs to Renal Cell Carcinoma

Positron emission tomography to assess hypoxia and perfusion in lung cancer

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Toward Prediction of Efficacy of Chemotherapy: A Proof of Concept Study in Lung Cancer Patients Using [11C]docetaxel and Positron Emission Tomography

Abstract: Purpose: Pharmacokinetics of docetaxel can be measured in vivo using positron emission tomography (PET) and a microdose of radiolabeled docetaxel ([ 11 C]docetaxel

Cited by 62 publications

References 29 publications

Molecular Drug Imaging: 89Zr-Bevacizumab PET in Children with Diffuse Intrinsic Pontine Glioma

Molecular Drug Imaging: 89Zr-Bevacizumab PET in Children with Diffuse Intrinsic Pontine Glioma

Acetazolamide Serves as Selective Delivery Vehicle for Dipeptide-Linked Drugs to Renal Cell Carcinoma

Positron emission tomography to assess hypoxia and perfusion in lung cancer

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Molecular Drug Imaging: ⁸⁹Zr-Bevacizumab PET in Children with Diffuse Intrinsic Pontine Glioma

Molecular Drug Imaging: ⁸⁹Zr-Bevacizumab PET in Children with Diffuse Intrinsic Pontine Glioma