A Phase I Study of a PARP1-targeted Topical Fluorophore for the Detection of Oral Cancer

Abstract Background. Visual inspection and biopsy is the current standard of care for oral cancer diagnosis, but is subject to misinterpretation and consequently to misdiagnosis. Topically applied PARPi-FL is a molecularly specific, fluorescent contrast-based approach that may fulfil the unmet need for a simple, in vivo, non-invasive, cost-effective, point-of-care method for the early diagnosis of oral cancer. Here, we present results from a phase I safety and feasibility study on fluorescent, topically applied PARPi-FL. Twelve patients with a histologically proven squamous cell carcinoma of the oral cavity (OSCC) gargled a PARPi-FL solution for 60 seconds (15 mL, 100 nM, 250 nM, 500 nM, or 1000 nM), followed by gargling a clearing solution for 60 seconds. Fluorescence measurements of the lesion and surrounding oral mucosa were taken before PARPi-FL application, after PARPi-FL application and after clearing. Blood pressure, oxygen levels, clinical chemistry and CBC were obtained before and after tracer administration. Results. PARPi-FL was well-tolerated by all patients without any safety concerns. When analyzing the fluorescence signal, all malignant lesions showed a significant differential in contrast after administration of PARPi-FL, with the highest increase occurring at the highest dose level (1000 nM), where all patients had a tumor-to-margin fluorescence signal ratio of > 3. A clearing step was essential to increase signal specificity, as it clears unbound PARPi-FL trapped in normal anatomical structures. PARPi-FL tumor cell specificity was confirmed by ex vivo tabletop confocal microscopy. We have demonstrated that the fluorescence signal arose from the nuclei of tumor cells, endorsing our macroscopic findings.Conclusions. A PARPi-FL swish & spit solution is a rapid and non-invasive diagnostic tool that preferentially localizes fluorescent contrast to OSCC. This technique holds promise for the early detection of OSCC based on in vivo optical evaluation and targeted biopsy of suspicious lesions in the oral cavity. Clinicaltrials.gov - NCT03085147, registered on March 21st, 2017.

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A Phase I Study of a PARP1-targeted Topical Fluorophore for the Detection of Oral Cancer

10.1101/2020.11.09.20228536 ◽

2020 ◽

Author(s):

Paula Demétrio de Souza França ◽

Susanne Kossatz ◽

Christian Brand ◽

Daniella Karassawa Zanoni ◽

Sheryl Roberts ◽

...

Keyword(s):

Oral Cancer ◽

Early Diagnosis ◽

Oral Cavity ◽

Point Of Care ◽

Cost Effective ◽

Standard Of Care ◽

Fluorescence Signal ◽

Current Standard ◽

Non Invasive

AbstractPurposeVisual inspection and biopsy is the current standard of care for oral cancer diagnosis, but is subject to misinterpretation and consequently to misdiagnosis. Topically applied PARPi-FL is a molecularly specific, fluorescent contrast-based approach that may fulfil the unmet need for a simple, in vivo, non-invasive, cost-effective, point-of-care method for the early diagnosis of oral cancer. Here, we present results from a phase I safety and feasibility study on fluorescent, topically applied PARPi-FL.Patients and MethodsTwelve patients with a histologically proven squamous cell carcinoma of the oral cavity (OSCC) gargled a PARPi-FL solution for 60 seconds (15 mL, 100 nM, 250 nM, 500 nM, or 1000 nM), followed by gargling a clearing solution for 60 seconds. Fluorescence measurements of the lesion and surrounding oral mucosa were taken before PARPi-FL application, after PARPi-FL application and after clearing. Blood pressure, oxygen levels, clinical chemistry and CBC were obtained before and after tracer administration.ResultsPARPi-FL was well-tolerated by all patients without any safety concerns. When analyzing the fluorescence signal, all malignant lesions showed a significant differential in contrast after administration of PARPi-FL, with the highest increase occurring at the highest dose level (1000 nM), where all patients had a tumor-to-margin fluorescence signal ratio of > 3. A clearing step was essential to increase signal specificity, as it clears unbound PARPi-FL trapped in normal anatomical structures. PARPi-FL tumor cell specificity was confirmed by ex vivo tabletop confocal microscopy. We have demonstrated that the fluorescence signal arose from the nuclei of tumor cells, endorsing our macroscopic findings.ConclusionsA PARPi-FL swish & spit solution is a rapid and non-invasive diagnostic tool that preferentially localizes fluorescent contrast to OSCC. This technique holds promise for the early detection of OSCC based on in vivo optical evaluation and targeted biopsy of suspicious lesions in the oral cavity.Translational RelevanceDespite their accessible location, oral cavity cancers are often diagnosed late, especially in low-resource areas where their incidence is typically high. The high prevalence of premalignant and benign oral lesions in these populations contributes to a number of issues that make early detection of oral cancer difficult: even in experienced hands, it can be difficult to differentiate cancer from premalignant or benign lesions during routine clinical examination; and biopsy-based histopathology, the current standard of care, is invasive, prone to sampling error, and requires geographic access to appropriate health care professionals, including a highly trained pathologist. While seemingly impenetrable economic and infrastructure barriers have confounded the early diagnosis of oral cancer for most of the world’s population, these could be circumvented by a simple, in vivo, non-invasive, cost-effective, point-of-care method of diagnosis. We are attempting to address this unmet clinical need by using topically applied PARPi-FL — a molecularly specific, fluorescent contrast-based approach — to detect oral cancer.FundingThis work was supported by National Institutes of Health grants P30 CA008748, R01 CA204441 (TR) and R43 CA228815 (CB and TR). Dr. Valero was sponsored by a grant from Fundación Alfonso Martín Escudero. The funding sources were not involved in study design, data collection and analysis, writing of the report, or the decision to submit this article for publication.Disclosure of Potential Conflicts of InterestC.B., S.K., S.P. and T.R. are shareholders of Summit Biomedical Imaging, LLC. S.K., S.P. and T.R. are co-inventors on PCT application WO2016164771. T.R. is co-inventor on PCT application WO2012074840. T.R. is a paid consultant for Theragnostics, Inc. All the other authors have no relevant conflict to declare. This arrangement has been reviewed and approved by Memorial Sloan Kettering Cancer Center in accordance with its conflict of interest policies.

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Clinical Chemistry: Platelet Reactivity Ex Vivo and In Vivo after Acute and Chronic Treatment with Sodium Caprylate

Scandinavian Journal of Clinical and Laboratory Investigation ◽

10.3109/00365517509068000 ◽

1975 ◽

Vol 35 (1) ◽

pp. 19-23 ◽

Cited By ~ 3

Author(s):

O. Tangen ◽

I. A. M. Wallenbeck ◽

D. Bergqvist

Keyword(s):

Chronic Treatment ◽

Ex Vivo ◽

Platelet Reactivity ◽

Clinical Chemistry ◽

Acute And Chronic Treatment ◽

Sodium Caprylate

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Faculty Opinions recommendation of In vivo and ex vivo comparative transcriptional profiling of invasive and non-invasive Candida albicans isolates identifies genes associated with tissue invasion.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1085792.538709 ◽

2007 ◽

Author(s):

John Perfect

Keyword(s):

Candida Albicans ◽

Ex Vivo ◽

Transcriptional Profiling ◽

Non Invasive ◽

Tissue Invasion

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Ex Vivo Assays of Dendritic Cell Activation and Cytokine Profiles as Predictors of In Vivo Effects in an Anti-Human CD40 Monoclonal Antibody ChiLob 7/4 Phase I Trial

Cancer Immunology Research ◽

10.1158/2326-6066.cir-13-0070 ◽

2013 ◽

Vol 2 (3) ◽

pp. 229-240 ◽

Cited By ~ 13

Author(s):

F. Chowdhury ◽

P.W. Johnson ◽

M.J. Glennie ◽

A.P. Williams

Keyword(s):

Monoclonal Antibody ◽

Dendritic Cell ◽

Phase I ◽

Cell Activation ◽

Phase I Trial ◽

Ex Vivo ◽

Dendritic Cell Activation ◽

Cytokine Profiles ◽

In Vivo Effects

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Mesenchymal stem cells accelerated growth and metastasis of neuroblastoma and preferentially homed towards both primary and metastatic loci in orthotopic neuroblastoma model

BMC Cancer ◽

10.1186/s12885-021-08090-2 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Jiao-Le Yu ◽

Shing Chan ◽

Marcus Kwong-Lam Fung ◽

Godfrey Chi-Fung Chan

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Primary Tumor ◽

Imaging System ◽

Ex Vivo ◽

Tumor Formation ◽

Human Neuroblastoma Cell ◽

Fluorescence Signal ◽

Human Neuroblastoma

Abstract Background Majority of neuroblastoma patients develop metastatic disease at diagnosis and their prognosis is poor with current therapeutic approach. Major challenges are how to tackle the mechanisms responsible for tumorigenesis and metastasis. Human mesenchymal stem cells (hMSCs) may be actively involved in the constitution of cancer microenvironment. Methods An orthotopic neuroblastoma murine model was utilized to mimic the clinical scenario. Human neuroblastoma cell line SK-N-LP was transfected with luciferase gene, which were inoculated with/without hMSCs into the adrenal area of SCID-beige mice. The growth and metastasis of neuroblastoma was observed by using Xenogen IVIS 100 in vivo imaging and evaluating gross tumors ex vivo. The homing of hMSCs towards tumor was analyzed by tracing fluorescence signal tagged on hMSCs using CRI Maestro™ imaging system. Results hMSCs mixed with neuroblastoma cells significantly accelerated tumor growth and apparently enhanced metastasis of neuroblastoma in vivo. hMSCs could be recruited by primary tumor and also become part of the tumor microenvironment in the metastatic lesion. The metastatic potential was consistently reduced in lung and tumor when hMSCs were pre-treated with stromal cell derived factor-1 (SDF-1) blocker, AMD3100, suggesting that the SDF-1/CXCR4 axis was one of the prime movers in the metastatic process. Conclusions hMSCs accelerated and facilitated tumor formation, growth and metastasis. Furthermore, the homing propensity of hMSCs towards both primary tumor and metastatic loci can also provide new therapeutic insights in utilizing bio-engineered hMSCs as vehicles for targeted anti-cancer therapy.

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Short-term plasticity of crassulacean acid metabolism expression in the epiphytic bromeliad Tillandsia usneoides

Functional Plant Biology ◽

10.1071/pp01214 ◽

2002 ◽

Vol 29 (6) ◽

pp. 749 ◽

Cited By ~ 13

Author(s):

Richard Haslam ◽

Anne Borland ◽

Howard Griffiths

Keyword(s):

Phase I ◽

Carbon Balance ◽

Crassulacean Acid Metabolism ◽

Acid Metabolism ◽

Rapid Change ◽

Co2 Uptake ◽

Short Term Plasticity ◽

Non Invasive ◽

Tillandsia Usneoides

This paper originates from a presentation at the IIIrd International Congress on Crassulacean Acid Metabolism, Cape Tribulation, Queensland, Australia, August 2001. The regulation and flexibility of the crassulacean acid metabolism (CAM) pathway has been investigated in the 'extreme epiphyte' Tillandsia usneoides (L.). Submerging strands of T. usneoides under water, thereby inhibiting the supply of atmospheric CO2, allowed non-invasive in vivo manipulation of the supply of CO2 during the nocturnal Phase I of CAM. Once the plants were removed from submersion, T. usneoides maintained open stomata, and net CO2 uptake occurred throughout most of the photoperiod. Variability in the expression of CAM allowed T. usneoides to compensate for restricted CO2 availability through Phase I of CAM by adjusting gas exchange rates through the photoperiod and subsequent dark period to maintain a constant internal supply of CO2 in the light. Furthermore, T. usneoides demonstrated a gradual, rather than rapid, change in phosphoenolpyruvate carboxylase (PEPC) activation across the day-night cycle, such that PEPC and Rubisco appear to work in tandem in order to maintain carbon balance for this extreme atmospheric bromeliad.

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New device permitting non‐invasive reversal of fetal endoscopic tracheal occlusion: ex‐vivo and in‐vivo study

Ultrasound in Obstetrics and Gynecology ◽

10.1002/uog.22132 ◽

2020 ◽

Vol 56 (4) ◽

pp. 522-531 ◽

Cited By ~ 1

Author(s):

D. Basurto ◽

N. Sananès ◽

E. Verbeken ◽

D. Sharma ◽

E. Corno ◽

...

Keyword(s):

Ex Vivo ◽

In Vivo Study ◽

Tracheal Occlusion ◽

New Device ◽

Non Invasive

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Quantitative PET imaging of PD-L1 expression in xenograft and syngeneic tumour models using a site-specifically labelled PD-L1 antibody

European Journal of Nuclear Medicine and Molecular Imaging ◽

10.1007/s00259-019-04646-4 ◽

2019 ◽

Vol 47 (5) ◽

pp. 1302-1313 ◽

Cited By ~ 5

Author(s):

Camilla Christensen ◽

Lotte K. Kristensen ◽

Maria Z. Alfsen ◽

Carsten H. Nielsen ◽

Andreas Kjaer

Keyword(s):

Pet Imaging ◽

Predictive Value ◽

Ex Vivo ◽

Response To Therapy ◽

Whole Body ◽

Therapeutic Monitoring ◽

Non Invasive ◽

Tumour Bearing ◽

Quantitative Pet

Abstract Purpose Despite remarkable clinical responses and prolonged survival across several cancers, not all patients benefit from PD-1/PD-L1 immune checkpoint blockade. Accordingly, assessment of tumour PD-L1 expression by immunohistochemistry (IHC) is increasingly applied to guide patient selection, therapeutic monitoring, and improve overall response rates. However, tissue-based methods are invasive and prone to sampling error. We therefore developed a PET radiotracer to specifically detect PD-L1 expression in a non-invasive manner, which could be of diagnostic and predictive value. Methods Anti-PD-L1 (clone 6E11, Genentech) was site-specifically conjugated with DIBO-DFO and radiolabelled with 89Zr (89Zr-DFO-6E11). 89Zr-DFO-6E11 was optimized in vivo by longitudinal PET imaging and dose escalation with excess unlabelled 6E11 in HCC827 tumour-bearing mice. Specificity of 89Zr-DFO-6E11 was evaluated in NSCLC xenografts and syngeneic tumour models with different levels of PD-L1 expression. In vivo imaging data was supported by ex vivo biodistribution, flow cytometry, and IHC. To evaluate the predictive value of 89Zr-DFO-6E11 PET imaging, CT26 tumour-bearing mice were subjected to external radiation therapy (XRT) in combination with PD-L1 blockade. Results 89Zr-DFO-6E11 was successfully labelled with a high radiochemical purity. The HCC827 tumours and lymphoid tissue were identified by 89Zr-DFO-6E11 PET imaging, and co-injection with 6E11 increased the relative tumour uptake and decreased the splenic uptake. 89Zr-DFO-6E11 detected the differences in PD-L1 expression among tumour models as evaluated by ex vivo methods. 89Zr-DFO-6E11 quantified the increase in PD-L1 expression in tumours and spleens of irradiated mice. XRT and anti-PD-L1 therapy effectively inhibited tumour growth in CT26 tumour-bearing mice (p < 0.01), and the maximum 89Zr-DFO-6E11 tumour-to-muscle ratio correlated with response to therapy (p = 0.0252). Conclusion PET imaging with 89Zr-DFO-6E11 is an attractive approach for specific, non-invasive, whole-body visualization of PD-L1 expression. PD-L1 expression can be modulated by radiotherapy regimens and 89Zr-DFO-6E11 PET is able to monitor these changes and predict the response to therapy in an immunocompetent tumour model.

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