Early evaluation of the effects of chemotherapy with longitudinal FDG small-animal PET in human testicular cancer xenografts: early flare response does not reflect refractory disease

Aide, Nicolas; Poulain, Laurent; Briand, Mélanie; Dutoit, Soizic; Allouche, Stéphane; Labiche, Alexandre; Ngo-Van, Aurélie; Nataf, Valérie; Batalla, A.; Gauduchon, Pascal; Talbot, Jean-Noël; Montravers, F.

doi:10.1007/s00259-008-0984-x

Cited by 19 publications

(19 citation statements)

References 27 publications

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“…increase in tumor FDG uptake was observed during the first week after chemotherapy, independent of tumor growth. This observation was followed by a rapid decrease in FDG uptake and subsequent tumor regression (39)(40)(41). The cause of the observed flare was uncertain; it was hypothesized that exposure to chemotherapy transiently induced glucose hypermetabolism in tumors, and cancer cells, inefficiently adapted to the induced metabolic stress, underwent apoptotic cell death through metabolic catastrophe (42,43).…”

Section: Discussionmentioning

confidence: 99%

Optical imaging of breast cancer oxyhemoglobin flare correlates with neoadjuvant chemotherapy response one day after starting treatment

Roblyer

Ueda

Cerussi

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

139

155

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Approximately 8-20% of breast cancer patients receiving neoadjuvant chemotherapy fail to achieve a measurable response and endure toxic side effects without benefit. Most clinical and imaging measures of response are obtained several weeks after the start of therapy. Here, we report that functional hemodynamic and metabolic information acquired using a noninvasive optical imaging method on the first day after neoadjuvant chemotherapy treatment can discriminate nonresponding from responding patients. Diffuse optical spectroscopic imaging was used to measure absolute concentrations of oxyhemoglobin, deoxyhemoglobin, water, and lipid in tumor and normal breast tissue of 24 tumors in 23 patients with untreated primary breast cancer. Measurements were made before chemotherapy, on day 1 after the first infusion, and frequently during the first week of therapy. Various multidrug, multicycle regimens were used to treat patients. Diffuse optical spectroscopic imaging measurements were compared with final postsurgical pathologic response. A statistically significant increase, or flare, in oxyhemoglobin was observed in partial responding (n = 11) and pathologic complete responding tumors (n = 8) on day 1, whereas nonresponders (n = 5) showed no flare and a subsequent decrease in oxyhemoglobin on day 1. Oxyhemoglobin flare on day 1 was adequate to discriminate nonresponding tumors from responding tumors. Very early measures of chemotherapy response are clinically convenient and offer the potential to alter treatment strategies, resulting in improved patient outcomes.in vivo imaging | near-infrared | diffuse optics | tissue spectroscopy | therapeutic monitoring

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Section: Discussionmentioning

confidence: 99%

Optical imaging of breast cancer oxyhemoglobin flare correlates with neoadjuvant chemotherapy response one day after starting treatment

Roblyer

Ueda

Cerussi

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

139

155

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“…PET imaging has been shown to be particularly useful for evaluating the efficacy of molecularly targeted therapies given either alone or in combination with conventional chemotherapies in preclinical studies (9,10). In clinical trials, PET can predict metabolic changes before tumor shrinkage, at a time when conventional imaging modalities and conventional criteria of evaluation (the criteria of the World Health Organization or the response evaluation criteria in solid tumors) are ineffective (11).…”

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confidence: 99%

¹⁸F-FLT PET as a Surrogate Marker of Drug Efficacy During mTOR Inhibition by Everolimus in a Preclinical Cisplatin-Resistant Ovarian Tumor Model

Aide¹,

Kinross²,

Cullinane³

et al. 2010

J Nucl Med

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Targeting the mammalian target of rapamycin (mTOR) pathway is a potential means of overcoming cisplatin resistance in ovarian cancer patients. Because mTOR inhibition affects cell proliferation, we aimed to study whether 39-deoxy-39-18 F-fluorothymidine ( 18 F-FLT) PET could be useful for monitoring early response to treatment with mTOR inhibitors in an animal model of cisplatin-resistant ovarian tumor. Methods: BALB/c nude mice bearing subcutaneous human SKOV3 ovarian cancer xenografts were treated with either the mTOR inhibitor everolimus (5 mg/kg) or vehicle, and 18 F-FLT PET was performed at baseline, day 2, and day 7 of treatment. 18 F-FLT uptake was evaluated by calculation of mean standardized uptake value (SUVmean) corrected for partial-volume effect. Ex vivo immunohistochemistry studies were performed on separate cohorts of mice treated as above and sacrificed at the same time points as for the PET studies. The ex vivo analysis included bromodeoxyuridine incorporation as a marker of cell proliferation, and phosphorylation of ribosomal protein S6 as a downstream marker of mTOR activation. Results: During the treatment period, no significant change in tumor 18 F-FLT uptake was observed in the vehicle group, whereas in everolimus-treated mice, 18 F-FLT SUVmean decreased by 33% (P 5 0.003) at day 2 and 66% (P , 0.001) at day 7, compared with baseline. Notably, the reduction of 18 F-FLT uptake observed at day 2 in the everolimus group preceded changes in tumor volume, and a significant difference in 18 F-FLT uptake was observed between vehicle and drug-treated tumors at both day 2 (P 5 0.0008) and day 7 (P 5 0.01). In ex vivo studies, everolimus treatment resulted in a 98% reduction in phosphorylated ribosomal protein S6 immunostaining at day 2 (P 5 0.02) and 91% reduction at day 7 (P 5 0.003), compared with the vehicle group. Bromodeoxyuridine incorporation was reduced by 65% at day 2 (not significant) and by 41% at day 7 (P 5 0.02) in drug versus vehicle groups. Conclusion: Reduction in 18 F-FLT uptake correlates well with the level of mTOR inhibition by everolimus in the SKOV3 ovarian tumor model. These data suggest that early treatment monitoring by 18 F-FLT PET may be of use in future preclinical or clinical trials evaluating treatment of cisplatinresistant ovarian tumors by mTOR inhibitors.

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“…Several positron emission tomography (PET) studies have been reported in mouse models of human cancer (16,17). The most frequently employed radiotracer was 18 (19,20).…”

Section: Introductionmentioning

confidence: 99%

A Personalized Preclinical Model to Evaluate the Metastatic Potential of Patient-Derived Colon Cancer Initiating Cells

Puig

Chicote

Tenbaum

et al. 2013

Clinical Cancer Research

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Purpose: Within the aim of advancing precision oncology, we have generated a collection of patientderived xenografts (PDX) characterized at the molecular level, and a preclinical model of colon cancer metastasis to evaluate drug-response and tumor progression.Experimental Design: We derived cells from 32 primary colorectal carcinomas and eight liver metastases and generated PDX annotated for their clinical data, gene expression, mutational, and histopathological traits. Six models were injected orthotopically into the cecum wall of NOD-SCID mice in order to evaluate metastasis. Three of them were treated with chemotherapy (oxaliplatin) and three with API2 to target AKT activity. Tumor growth and metastasis progression were analyzed by positron emission tomography (PET).Results: Patient-derived cells generated tumor xenografts that recapitulated the same histopathological and genetic features as the original patients' carcinomas. We show an 87.5% tumor take rate that is one of the highest described for implanted cells derived from colorectal cancer patients. Cecal injection generated primary carcinomas and distant metastases. Oxaliplatin treatment prevented metastasis and API2 reduced tumor growth as evaluated by PET.Conclusions: Our improved protocol for cancer cell engraftment has allowed us to build a rapidly expanding collection of colorectal PDX, annotated for their clinical data, gene expression, mutational, and histopathological statuses. We have also established a mouse model for metastatic colon cancer with patient-derived cells in order to monitor tumor growth, metastasis evolution, and response to treatment by PET. Our PDX models could become the best preclinical approach through which to validate new biomarkers or investigate the metastatic potential and drug-response of individual patients.

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Early evaluation of the effects of chemotherapy with longitudinal FDG small-animal PET in human testicular cancer xenografts: early flare response does not reflect refractory disease

Abstract: FDG PET may be useful in the early evaluation of treatment in patients with testicular cancer. In our model, a very early increased [(18)F]-FDG uptake was related to a transient cell cycle arrest and early stage apoptosis but did not reveal refractory disease.

Cited by 19 publications

References 27 publications

Optical imaging of breast cancer oxyhemoglobin flare correlates with neoadjuvant chemotherapy response one day after starting treatment

Optical imaging of breast cancer oxyhemoglobin flare correlates with neoadjuvant chemotherapy response one day after starting treatment

¹⁸F-FLT PET as a Surrogate Marker of Drug Efficacy During mTOR Inhibition by Everolimus in a Preclinical Cisplatin-Resistant Ovarian Tumor Model

A Personalized Preclinical Model to Evaluate the Metastatic Potential of Patient-Derived Colon Cancer Initiating Cells

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Early evaluation of the effects of chemotherapy with longitudinal FDG small-animal PET in human testicular cancer xenografts: early flare response does not reflect refractory disease

Abstract: FDG PET may be useful in the early evaluation of treatment in patients with testicular cancer. In our model, a very early increased [(18)F]-FDG uptake was related to a transient cell cycle arrest and early stage apoptosis but did not reveal refractory disease.

Cited by 19 publications

References 27 publications

Optical imaging of breast cancer oxyhemoglobin flare correlates with neoadjuvant chemotherapy response one day after starting treatment

Optical imaging of breast cancer oxyhemoglobin flare correlates with neoadjuvant chemotherapy response one day after starting treatment

18F-FLT PET as a Surrogate Marker of Drug Efficacy During mTOR Inhibition by Everolimus in a Preclinical Cisplatin-Resistant Ovarian Tumor Model

A Personalized Preclinical Model to Evaluate the Metastatic Potential of Patient-Derived Colon Cancer Initiating Cells

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¹⁸F-FLT PET as a Surrogate Marker of Drug Efficacy During mTOR Inhibition by Everolimus in a Preclinical Cisplatin-Resistant Ovarian Tumor Model