scholarly journals High-resolution positron emission microscopy of patient-derived tumor organoids

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Syamantak Khan ◽  
June Ho Shin ◽  
Valentina Ferri ◽  
Ning Cheng ◽  
Julia E. Noel ◽  
...  
Keyword(s):  
Imaging Biomarkers ◽  
Drug Candidates ◽  
Treatment Regimens ◽  
Uptake Pathway ◽  
Positron Emission ◽  
Glycolytic Activity ◽  
Microscopy Method ◽  
Emission Microscopy ◽  
Tumor Organoids

AbstractTumor organoids offer new opportunities for translational cancer research, but unlike animal models, their broader use is hindered by the lack of clinically relevant imaging endpoints. Here, we present a positron-emission microscopy method for imaging clinical radiotracers in patient-derived tumor organoids with spatial resolution 100-fold better than clinical positron emission tomography (PET). Using this method, we quantify 18F-fluorodeoxyglucose influx to show that patient-derived tumor organoids recapitulate the glycolytic activity of the tumor of origin, and thus, could be used to predict therapeutic response in vitro. Similarly, we measure sodium-iodine symporter activity using 99mTc- pertechnetate and find that the iodine uptake pathway is functionally conserved in organoids derived from thyroid carcinomas. In conclusion, organoids can be imaged using clinical radiotracers, which opens new possibilities for identifying promising drug candidates and radiotracers, personalizing treatment regimens, and incorporating clinical imaging biomarkers in organoid-based co-clinical trials.

527 Tumor organoid and immune cell co-culture system potentiates immuno-oncology drug development

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A563-A563
Author(s):  
Hongjuan Zhang ◽  
Jun Zhou ◽  
Shuang Zhu ◽  
Jia Zheng ◽  
Limei Shang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Cells ◽  
Luciferase Activity ◽  
Drug Candidates ◽  
Car T Cells ◽  
Car T ◽  
Oncology Drug Development ◽  
Tumor Organoids

BackgroundPatient-derived organoids (PDOs) are derived from adult epithelial stem cell with self-renewal, organisation and differentiation properties, reflecting the original 3D organ-like or tissue-like structure and morphology in vitro. PDOs also faithfully recapitulate the genetic modifications and phenotypical features of original tumors, making them an attractive preclinical models for oncology drug development. However, modeling the tumor microenvironment (TME) in vitro remains a challenge due to the lack of stromal and immune cells. In this study, we reconstituted component of the TME through co-culture of tumor organoids with various immune cells in vitro to assess the immune modulatory and tumor killing effects of immuno-oncology (IO) drug candidates such as therapeutic monoclonal antibodies, bispecific T cell engagers and CAR-T cells.MethodsUsing the Hubrecht organoid technology (HUB) protocols we have established a biobank of tumor and normal organoids, which closely resemble the genetic and morphologic features of original organs from multiple different tissue types. This large and diverse biobank of organoids can act as surrogates for individual patients making them suitable for patient population studies including evaluating the response to IO drug candidates in vitro.ResultsWe co-cultured organoids expressing tumor associated antigen (TAA) of interest with bispecific T cell engagers and CAR-T cells recognizing the TAAs. Our data demonstrated antigen-specific T cell killing of tumor organoids and tumor antigen reactivity of bispecific antibody activated T cells and CAR-T. We engineered tumor organoids to express CD19 and a luciferase reporter gene and measured luciferase activity to monitor the growth and killing of tumor organoids by CD19 CAR-T cells. The luciferase activity in organoids reflected the killing efficiency in a very sensitive, robust and high through-put manner. Immune checkpoint molecules are differentially expressed on individual tumor organoids and we evaluated the potency of immune check blockade using tumor organoids cocultured with allogenic T cells. Killing of tumor organoids and T cell activation was enhanced by PD-1/PD-L1 blockade. We profiled the expression of immune check point molecules on our banked tumor organoids which will provide a valuable resource to choose tumor models and cancer types for preclinical testing of IO drugs.ConclusionsIn conclusion, we demonstrated the feasibility of in vitro patient-derived model system in the field of IO research using tumor organoid co-culture with immune cells, and their application in IO target and drug discovery.

scholarly journals Combining PET Biodistribution and Equilibrium Dialysis Assays to Assess the Free Brain Concentration and BBB Transport of CNS Drugs

2012 ◽  
Vol 32 (5) ◽  
pp. 874-883 ◽  
Author(s):  
Roger N Gunn ◽  
Scott G Summerfield ◽  
Cristian A Salinas ◽  
Kevin D Read ◽  
Qi Guo ◽  
...  
Keyword(s):  
Drug Development ◽  
Human Brain ◽  
Concentration Gradient ◽  
Equilibrium Dialysis ◽  
Active Efflux ◽  
Brain Concentration ◽  
Drug Candidates ◽  
Positron Emission

The passage of drugs in and out of the brain is controlled by the blood—brain barrier (BBB), typically, using either passive diffusion across a concentration gradient or active transport via a protein carrier. In-vitro and preclinical measurements of BBB penetration do not always accurately predict the in-vivo situation in humans. Thus, the ability to assay the concentration of novel drug candidates in the human brain in vivo provides valuable information for derisking of candidate molecules early in drug development. Here, positron emission tomography (PET) measurements are combined with in-vitro equilibrium dialysis assays to enable assessment of transport and estimation of the free brain concentration in vivo. The PET and equilibrium dialysis data were obtained for 36 compounds in the pig. Predicted P-glycoprotein (P-gp) status of the compounds was consistent with the PET/equilibrium dialysis results. In particular, Loperamide, a well-known P-gp substrate, exhibited a significant concentration gradient consistent with active efflux and after inhibition of the P-gp process the gradient was removed. The ability to measure the free brain concentration and assess transport of novel compounds in the human brain with combined PET and equilibrium dialysis assays can be a useful tool in central nervous system (CNS) drug development.

scholarly journals High-resolution positron emission microscopy of patient-derived tumor organoids

2020 ◽  
Author(s):  
Syamantak Khan ◽  
June Ho Shin ◽  
Valentina Ferri ◽  
Ning Cheng ◽  
Julia E. Noel ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Metabolic Imaging ◽  
Positron Emission ◽  
Pet Ct ◽  
Microscopy Method ◽  
Dose Dependent Decrease ◽  
Personalized Approach ◽  
Dose Dependent ◽  
Tumor Organoids ◽  
Better Than

AbstractOrganoid tumor models have found application in a growing array of cancer studies due to their ability to closely recapitulate the structural and functional characteristics of solid tumors. However, organoids are too small to be compatible with common radiological tools used in oncology clinics. Here, we present a microscopy method to image 18F-fluorodeoxyglucose in patient-derived tumor organoids with spatial resolution up to 100-fold better than that of clinical positron emission tomography (PET). When combined with brightfield imaging, this metabolic imaging approach functionally mirrors clinical PET/CT scans and provides a quantitative readout of cell glycolysis. In particular, the specific avidity of a tumor for FDG, or lack thereof, was maintained when the tumor cells were grown ex vivo as tumor organoids. In addition, cisplatin treatment caused a dose-dependent decrease in the metabolic activity of these organoids, with the exception of one patient whose tumor was also resistant to cisplatin treatment. Thus, FDG-imaging of organoids could be used to predict the response of individual patients to different treatments and provide a more personalized approach to cancer care.

Abstract B08: High-resolution positron emission microscopy of patient-derived tumor organoids

2020 ◽  
Author(s):  
Syamantak Khan ◽  
June Ho Shin ◽  
Ning Cheng ◽  
Calvin Kuo ◽  
John Sunwoo ◽  
...  
Keyword(s):  
High Resolution ◽  
Positron Emission ◽  
Emission Microscopy ◽  
Tumor Organoids

Peculiarities of the course of type I allergic reactions in patients with blood diseases

2020 ◽  
pp. 40-50
Author(s):  
A. Nikitina
Keyword(s):  
Search Engines ◽  
Anaphylactic Shock ◽  
Type I ◽  
Allergic Reactions ◽  
Common Cause ◽  
Blood Diseases ◽  
Treatment Regimens ◽  
Modern Methods

Analysis of literature data presented in search engines — Elibrary, PubMed, Cochrane — concerning the risk of developing type I allergic reactions in patients with blood diseases is presented. It is shown that the most common cause of type I allergic reactions is drugs included in the treatment regimens of this category of patients. The article presents statistics on the increase in the number of drug allergies leading to cases of anaphylactic shock in patients with blood diseases. Modern methods for the diagnosis of type I allergic reactions in vivo and in vitro are considered.

Flavonoids as P-gp Inhibitors: A Systematic Review of SARs

2019 ◽  
Vol 26 (25) ◽  
pp. 4799-4831 ◽  
Author(s):  
Jiahua Cui ◽  
Xiaoyang Liu ◽  
Larry M.C. Chow
Keyword(s):  
Molecular Mechanisms ◽  
Metastatic Cancer ◽  
Drug Candidates ◽  
Chemical Structures ◽  
Transporter Family ◽  
Promising Area ◽  
New Generation ◽  
Nontoxic Inhibitors

P-glycoprotein, also known as ABCB1 in the ABC transporter family, confers the simultaneous resistance of metastatic cancer cells towards various anticancer drugs with different targets and diverse chemical structures. The exploration of safe and specific inhibitors of this pump has always been the pursuit of scientists for the past four decades. Naturally occurring flavonoids as benzopyrone derivatives were recognized as a class of nontoxic inhibitors of P-gp. The recent advent of synthetic flavonoid dimer FD18, as a potent P-gp modulator in reversing multidrug resistance both in vitro and in vivo, specifically targeted the pseudodimeric structure of the drug transporter and represented a new generation of inhibitors with high transporter binding affinity and low toxicity. This review concerned the recent updates on the structure-activity relationships of flavonoids as P-gp inhibitors, the molecular mechanisms of their action and their ability to overcome P-gp-mediated MDR in preclinical studies. It had crucial implications on the discovery of new drug candidates that modulated the efflux of ABC transporters and also provided some clues for the future development in this promising area.

Review on the Clinical Pharmacology of Hydroxychloroquine Sulfate for the Treatment of COVID-19

2020 ◽  
Vol 21 (6) ◽  
pp. 427-435 ◽  
Author(s):  
Cheng Cui ◽  
Siqi Tu ◽  
Valerie Sia Jie En ◽  
Xiaobei Li ◽  
Xueting Yao ◽  
...  
Keyword(s):  
Drug Interactions ◽  
Clinical Efficacy ◽  
Relevant Literature ◽  
The United States ◽  
Efficacy And Safety ◽  
Open Label ◽  
Infected People ◽  
Treatment Regimens ◽  
Therapeutic Drugs

Background: As the number of severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) infected people is greatly increasing worldwide, the international medical situation becomes very serious. Potential therapeutic drugs, vaccine and stem cell replacement methods are emerging, so it is urgent to find specific therapeutic drugs and the best treatment regimens. After the publications on hydroxychloroquine (HCQ) with anti- SARS-COV-2 activity in vitro, a small, non-randomized, open-label clinical trial showed that HCQ treatment was significantly associated with reduced viral load in patients with coronavirus disease-19 (COVID-19). Meanwhile, a large prophylaxis study of HCQ sulfate for COVID-19 has been initiated in the United States. HCQ offered a promising efficacy in the treatment of COVID-19, but the optimal administration is still being explored. Methods: We used the keyword "hydroxychloroquine" to conduct a literature search in PubMed to collect relevant literature on the mechanism of action of HCQ, its clinical efficacy and safety, pharmacokinetic characteristics, precautions for clinical use and drug interactions to extract and organize information. Results: This paper reviews the mechanism, clinical efficacy and safety, pharmacokinetic characteristics, exposureresponse relationship and precautions and drug interactions of HCQ, and summarizes dosage recommendations for HCQ sulfate. Conclusion: It has been proved that HCQ, which has an established safety profile, is effective against SARS-CoV-2 with sufficient pre-clinical rationale and evidence. Data from high-quality clinical trials are urgently needed worldwide.

Current Approaches to Drug Discovery for Chagas Disease: Methodological Advances

2019 ◽  
Vol 22 (8) ◽  
pp. 509-520
Author(s):  
Cauê B. Scarim ◽  
Chung M. Chin
Keyword(s):  
Drug Discovery ◽  
Chagas Disease ◽  
Drug Candidates ◽  
Lead Compounds ◽  
New Drug ◽  
Compound Libraries ◽  
Screening Assays ◽  
Cruzi Infection

Background: In recent years, there has been an improvement in the in vitro and in vivo methodology for the screening of anti-chagasic compounds. Millions of compounds can now have their activity evaluated (in large compound libraries) by means of high throughput in vitro screening assays. Objective: Current approaches to drug discovery for Chagas disease. Method: This review article examines the contribution of these methodological advances in medicinal chemistry in the last four years, focusing on Trypanosoma cruzi infection, obtained from the PubMed, Web of Science, and Scopus databases. Results: Here, we have shown that the promise is increasing each year for more lead compounds for the development of a new drug against Chagas disease. Conclusion: There is increased optimism among those working with the objective to find new drug candidates for optimal treatments against Chagas disease.

scholarly journals Targeting RON receptor tyrosine kinase for treatment of advanced solid cancers: antibody–drug conjugates as lead drug candidates for clinical trials

2020 ◽  
Vol 12 ◽  
pp. 175883592092006
Author(s):  
Hang-Ping Yao ◽  
Sreedhar Reddy Suthe ◽  
Xiang-Min Tong ◽  
Ming-Hai Wang
Keyword(s):  
Clinical Trials ◽  
Tyrosine Kinase ◽  
Receptor Tyrosine Kinase ◽  
Targeted Therapeutics ◽  
Antibody Drug Conjugates ◽  
Drug Candidates ◽  
Drug Conjugates ◽  
Ron Receptor ◽  
Antibody Drug

The recepteur d’origine nantais (RON) receptor tyrosine kinase, belonging to the mesenchymal-to-epithelial transition proto-oncogene family, has been implicated in the pathogenesis of cancers derived from the colon, lung, breast, and pancreas. These findings lay the foundation for targeting RON for cancer treatment. However, development of RON-targeted therapeutics has not gained sufficient attention for the last decade. Although therapeutic monoclonal antibodies (TMABs) targeting RON have been validated in preclinical studies, results from clinical trials have met with limited success. This outcome diminishes pharmaceutical enthusiasm for further development of RON-targeted therapeutics. Recently, antibody–drug conjugates (ADCs) targeting RON have drawn special attention owing to their increased therapeutic activity. The rationale for developing anti-RON ADCs is based on the observation that cancer cells are not sufficiently addicted to RON signaling for survival. Thus, TMAB-mediated inhibition of RON signaling is ineffective for clinical application. In contrast, anti-RON ADCs combine a target-specific antibody with potent cytotoxins for cancer cell killing. This approach not only overcomes the shortcomings in TMAB-targeted therapies but also holds the promise for advancing anti-RON ADCs into clinical trials. In this review, we discuss the latest advancements in the development of anti-RON ADCs for targeted cancer therapy including drug conjugation profile, pharmacokinetic properties, cytotoxic effect in vitro, efficacy in tumor models, and toxicological activities in primates.

scholarly journals Simple Thalidomide Analogs in Melanoma: Synthesis and Biological Activity

2021 ◽  
Vol 11 (13) ◽  
pp. 5823
Author(s):  
Alexia Barbarossa ◽  
Alessia Catalano ◽  
Jessica Ceramella ◽  
Alessia Carocci ◽  
Domenico Iacopetta ◽  
...  
Keyword(s):  
Anticancer Agent ◽  
Ring System ◽  
In Vitro Assays ◽  
Tubulin Polymerization ◽  
Cytotoxic Effects ◽  
Ongoing Research ◽  
Drug Candidates ◽  
Small Series ◽  
Clinical Interest

Thalidomide is an old well-known drug that is still of clinical interest, despite its teratogenic activities, due to its antiangiogenic and immunomodulatory properties. Therefore, efforts to design safer and effective thalidomide analogs are continually ongoing. Research studies on thalidomide analogs have revealed that the phthalimide ring system is an essential pharmacophoric fragment; thus, many phthalimidic compounds have been synthesized and evaluated as anticancer drug candidates. In this study, a panel of selected in vitro assays, performed on a small series of phthalimide derivatives, allowed us to characterize compound 2k as a good anticancer agent, acting on A2058 melanoma cell line, which causes cell death by apoptosis due to its capability to inhibit tubulin polymerization. The obtained data were confirmed by in silico assays. No cytotoxic effects on normal cells have been detected for this compound that proves to be a valid candidate for further investigations to achieve new insights on possible mechanism of action of this class of compounds as anticancer drugs.

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