Patient-Derived Tumor Organoids for Drug Repositioning in Cancer Care: A Promising Approach in the Era of Tailored Treatment

Malignancies heterogeneity represents a critical issue in cancer care, as it often causes therapy resistance and tumor relapse. Organoids are three-dimensional (3D) miniaturized representations of selected tissues within a dish. Lately, organoid technology has been applied to oncology with growing success and Patients Derived Tumor Organoids (PDTOs) constitute a novel available tool which fastens cancer research. PDTOs are in vitro models of cancer, and importantly, they can be used as a platform to validate the efficacy of anti-cancer drugs. For that reason, they are currently utilized in clinics as emerging in vitro screening technology to tailor the therapy around the patient, with the final goal of beating cancer resistance and recurrence. In this sense, PDTOs biobanking is widely used and PDTO-libraries are helping the discovery of novel anticancer molecules. Moreover, they represent a good model to screen and validate compounds employed for other pathologies as off-label drugs potentially repurposed for the treatment of tumors. This will open up novel avenues of care thus ameliorating the life expectancy of cancer patients. This review discusses the present advancements in organoids research applied to oncology, with special attention to PDTOs and their translational potential, especially for anti-cancer drug testing, including off-label molecules.

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Bioprinting of patient-derived in vitro intrahepatic cholangiocarcinoma tumor model: establishment, evaluation and anti-cancer drug testing

Biofabrication ◽

10.1088/1758-5090/aba0c3 ◽

2020 ◽

Vol 12 (4) ◽

pp. 045014

Author(s):

Shuangshuang Mao ◽

Jianyu He ◽

Yu Zhao ◽

Tiankun Liu ◽

Feihu Xie ◽

...

Keyword(s):

Intrahepatic Cholangiocarcinoma ◽

Drug Testing ◽

Tumor Model ◽

Cancer Drug ◽

Anti Cancer

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Optimization and Validation of a Novel Three-Dimensional Co-Culture System in Decellularized Human Liver Scaffold for the Study of Liver Fibrosis and Cancer

Cancers ◽

10.3390/cancers13194936 ◽

2021 ◽

Vol 13 (19) ◽

pp. 4936

Author(s):

Kessarin Thanapirom ◽

Elisabetta Caon ◽

Margarita Papatheodoridi ◽

Luca Frenguelli ◽

Walid Al-Akkad ◽

...

Keyword(s):

Protein Expression ◽

Human Liver ◽

Drug Testing ◽

Three Dimensional ◽

Cancer Drug ◽

3D Scaffolds ◽

Stat3 Phosphorylation ◽

Anti Cancer ◽

Tgf Β1

The introduction of new preclinical models for in vitro drug discovery and testing based on 3D tissue-specific extracellular matrix (ECM) is very much awaited. This study was aimed at developing and validating a co-culture model using decellularized human liver 3D ECM scaffolds as a platform for anti-fibrotic and anti-cancer drug testing. Decellularized 3D scaffolds obtained from healthy and cirrhotic human livers were bioengineered with LX2 and HEPG2 as single and co-cultures for up to 13 days and validated as a new drug-testing platform. Pro-fibrogenic markers and cancer phenotypic gene/protein expression and secretion were differently affected when single and co-cultures were exposed to TGF-β1 with specific ECM-dependent effects. The anti-fibrotic efficacy of Sorafenib significantly reduced TGF-β1-induced pro-fibrogenic effects, which coincided with a downregulation of STAT3 phosphorylation. The anti-cancer efficacy of Regorafenib was significantly reduced in 3D bioengineered cells when compared to 2D cultures and dose-dependently associated with cell apoptosis by cleaved PARP-1 activation and P-STAT3 inhibition. Regorafenib reversed TGF-β1-induced P-STAT3 and SHP-1 through induction of epithelial mesenchymal marker E-cadherin and downregulation of vimentin protein expression in both co-cultures engrafting healthy and cirrhotic 3D scaffolds. In their complex, the results of the study suggest that this newly proposed 3D co-culture platform is able to reproduce the natural physio-pathological microenvironment and could be employed for anti-fibrotic and anti-HCC drug screening.

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3D Bioprinted Vascularized Tumour for Drug Testing

International Journal of Molecular Sciences ◽

10.3390/ijms21082993 ◽

2020 ◽

Vol 21 (8) ◽

pp. 2993 ◽

Cited By ~ 6

Author(s):

Seokgyu Han ◽

Sein Kim ◽

Zhenzhong Chen ◽

Hwa Kyoung Shin ◽

Seo-Yeon Lee ◽

...

Keyword(s):

Blood Vessel ◽

Blood Vessels ◽

Drug Testing ◽

Tumour Size ◽

Combined Treatment ◽

Cancer Drug ◽

Angiogenic Inhibitor ◽

Anti Cancer

An in vitro screening system for anti-cancer drugs cannot exactly reflect the efficacy of drugs in vivo, without mimicking the tumour microenvironment (TME), which comprises cancer cells interacting with blood vessels and fibroblasts. Additionally, the tumour size should be controlled to obtain reliable and quantitative drug responses. Herein, we report a bioprinting method for recapitulating the TME with a controllable spheroid size. The TME was constructed by printing a blood vessel layer consisting of fibroblasts and endothelial cells in gelatine, alginate, and fibrinogen, followed by seeding multicellular tumour spheroids (MCTSs) of glioblastoma cells (U87 MG) onto the blood vessel layer. Under MCTSs, sprouts of blood vessels were generated and surrounding MCTSs thereby increasing the spheroid size. The combined treatment involving the anti-cancer drug temozolomide (TMZ) and the angiogenic inhibitor sunitinib was more effective than TMZ alone for MCTSs surrounded by blood vessels, which indicates the feasibility of the TME for in vitro testing of drug efficacy. These results suggest that the bioprinted vascularized tumour is highly useful for understanding tumour biology, as well as for in vitro drug testing.

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Development, validation and pilot screening of an in vitro multi-cellular three-dimensional cancer spheroid assay for anti-cancer drug testing

Bioorganic & Medicinal Chemistry ◽

10.1016/j.bmc.2012.12.007 ◽

2013 ◽

Vol 21 (4) ◽

pp. 922-931 ◽

Cited By ~ 24

Author(s):

Rati Lama ◽

Lin Zhang ◽

Janine M. Naim ◽

Jennifer Williams ◽

Aimin Zhou ◽

...

Keyword(s):

Drug Testing ◽

Three Dimensional ◽

Cancer Drug ◽

Anti Cancer

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Stereocomplexation Assisted Assembly of Poly(γ-glutamic Acid)-graft-polylactide Nano-micelles and Their Efficacy as Anticancer Drug Carrier

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520617666170911170104 ◽

2018 ◽

Vol 18 (2) ◽

pp. 302-311

Author(s):

Shulin Dai ◽

Yucheng Feng ◽

Shuyi Li ◽

Yuxiao Chen ◽

Meiqing Liu ◽

...

Keyword(s):

Glutamic Acid ◽

Drug Carrier ◽

Drug Loading ◽

Drug Carriers ◽

Cancer Drug ◽

Drug Release Profile ◽

Sustained Drug Release ◽

Anti Cancer ◽

Physical Interactions

Background: Micelles as drug carriers are characterized by their inherent instability due to the weak physical interactions that facilitate the self-assembly of amphiphilic block copolymers. As one of the strong physical interactions, the stereocomplexation between the equal molar of enantiomeric polylactides, i.e., the poly(L-lactide) (PLLA) and poly(D-lactide) (PDLA), may be harnessed to obtain micelles with enhanced stability and drug loading capacity and consequent sustained release. </P><P> Aims/Methods: In this paper, stereocomplexed micelles gama-PGA-g-PLA micelles) were fabricated from the stereocomplexation between poly(gama-glutamic acid)-graft-PLLA gama-PGA-g-PLA) and poly(gamaglutamic acid)-graft-PDLA gama-PGA-g-PLA). These stereocomplexed micelles exhibited a lower CMC than the corresponding enantiomeric micelles. Result: Furthermore, they showed higher drug loading content and drug loading efficiency in addition to more sustained drug release profile in vitro. In vivo imaging confirmed that the DiR-encapsulated stereocomplexed gama-PGA-g-PLA micelles can deliver anti-cancer drug to tumors with enhanced tissue penetration. Overall, gama-PGA-g-PLA micelles exhibited greater anti-cancer effects as compared with the free drug and the stereocomplexation may be a promising strategy for fabrication of anti-cancer drug carriers with significantly enhanced efficacy.

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Prevascularized, Co-Culture Model for Breast Cancer Drug Development

ASME 2012 Summer Bioengineering Conference, Parts A and B ◽

10.1115/sbc2012-80409 ◽

2012 ◽

Author(s):

Lauren Marshall ◽

Isabel Löwstedt ◽

Paul Gatenholm ◽

Joel Berry

Keyword(s):

Breast Cancer ◽

Drug Development ◽

Three Dimensional ◽

Human Tumor ◽

3D Models ◽

Cancer Drug ◽

Cancer Therapies ◽

Anti Cancer

The objective of this study was to create 3D engineered tissue models to accelerate identification of safe and efficacious breast cancer drug therapies. It is expected that this platform will dramatically reduce the time and costs associated with development and regulatory approval of anti-cancer therapies, currently a multi-billion dollar endeavor [1]. Existing two-dimensional (2D) in vitro and in vivo animal studies required for identification of effective cancer therapies account for much of the high costs of anti-cancer medications and health insurance premiums borne by patients, many of whom cannot afford it. An emerging paradigm in pharmaceutical drug development is the use of three-dimensional (3D) cell/biomaterial models that will accurately screen novel therapeutic compounds, repurpose existing compounds and terminate ineffective ones. In particular, identification of effective chemotherapies for breast cancer are anticipated to occur more quickly in 3D in vitro models than 2D in vitro environments and in vivo animal models, neither of which accurately mimic natural human tumor environments [2]. Moreover, these 3D models can be multi-cellular and designed with extracellular matrix (ECM) function and mechanical properties similar to that of natural in vivo cancer environments [3].

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Frontiers in Anti-cancer Drug Discovery: Challenges and Perspectives of Metformin as Anti-angiogenic Add-on Therapy in Glioblastoma

10.20944/preprints202111.0531.v1 ◽

2021 ◽

Author(s):

Laura Guarnaccia ◽

Stefania Elena Navone ◽

Matteo Maria Masseroli ◽

Melissa Balsamo ◽

Manuela Caroli ◽

...

Keyword(s):

Target Therapy ◽

Cancer Drug ◽

Cancer Drug Discovery ◽

Average Survival ◽

Anti Cancer ◽

Tumor Neovascularization ◽

Novel Therapeutic Strategies

Glioblastoma (GBM) is the most common primitive tumor in adult central nervous system (CNS), classified as grade IV according to WHO 2016 classification. GBM shows a poor prognosis with an average survival of approximately 15 months, representing an extreme therapeutic challenge. One of its distinctive and aggressive features is aberrant angiogenesis, which drives tumor neovascularization, representing a promising candidate for molecular target therapy. Although several pre-clinical studies and clinical trials have shown promising results, anti-angiogenic drugs have not led to a significant improvement in overall survival (OS), suggesting the necessity of identifying novel therapeutic strategies. Metformin, an anti-hyperglycemic drug of the Biguanides family, used as first line treatment in Type 2 Diabetes Mellitus (T2DM), demonstrated in vitro and in vivo antitumoral efficacy in many different tumors, including GBM. From this evidence, a process of repurposing of the drug has begun, leading to the demonstration of the inhibition of various oncopromoter mechanisms and, consequently, to the identification of the molecular pathways involved. Here, we review and discuss the potential metformin’s antitumoral effects on GBM, inspecting if it could properly act as an anti-angiogenic compound to be considered as a safely add-on therapy in the treatment and management of GBM patients.

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Coherent Raman Scattering Microscopy in Oncology Pharmacokinetic Research

Frontiers in Pharmacology ◽

10.3389/fphar.2021.630167 ◽

2021 ◽

Vol 12 ◽

Author(s):

Junjie Zeng ◽

Wenying Zhao ◽

Shuhua Yue

Keyword(s):

Raman Scattering ◽

High Speed ◽

Cancer Drug ◽

Cancer Drugs ◽

High Speed Imaging ◽

Coherent Raman Scattering ◽

Anti Cancer ◽

Coherent Raman

The high attrition rates of anti-cancer drugs during clinical development remains a bottleneck problem in pharmaceutical industry. This is partially due to the lack of quantitative, selective, and rapid readouts of anti-cancer drug activity in situ with high resolution. Although fluorescence microscopy has been commonly used in oncology pharmacological research, fluorescent labels are often too large in size for small drug molecules, and thus may disturb the function or metabolism of these molecules. Such challenge can be overcome by coherent Raman scattering microscopy, which is capable of chemically selective, highly sensitive, high spatial resolution, and high-speed imaging, without the need of any labeling. Coherent Raman scattering microscopy has tremendously improved the understanding of pharmaceutical materials in the solid state, pharmacokinetics of anti-cancer drugs and nanocarriers in vitro and in vivo. This review focuses on the latest applications of coherent Raman scattering microscopy as a new emerging platform to facilitate oncology pharmacokinetic research.

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