Cancer-on-a-chip for Drug Screening

: The oncology pharmaceutical research spent a shocking amount of money on target validation and drug optimization in preclinical models because many oncology drugs fail during clinical trial phase III. One of the most important reasons for oncology drug failures in clinical trials may due to the poor predictive tool of existing preclinical models. Therefore, in cancer research and personalized medicine field, it is critical to improve the effectiveness of preclinical predictions of the drug response of patients to therapies and to reduce costly failures in clinical trials. Three dimensional (3D) tumor models combine micro-manufacturing technologies mimic critical physiologic parameters present in vivo, including complex multicellular architecture with multicellular arrangement and extracellular matrix deposition, packed 3D structures with cell–cell interactions, such as tight junctions, barriers to mass transport of drugs, nutrients and other factors, which are similar to in vivo tumor tissues. These systems provide a solution to mimic the physiological environment for improving predictive accuracy in oncology drug discovery. : his review gives an overview of the innovations, development and limitations of different types of tumor-like construction techniques such as self-assemble spheroid formation, spheroids formation by micro-manufacturing technologies, micro-dissected tumor tissues and tumor organoid. Combination of 3D tumor-like construction and microfluidic techniques to achieve tumor on a chip for in vitro tumor environment modeling and drug screening were all included. Eventually, developmental directions and technical challenges in the research field are also discussed. We believe tumor on chip models have provided better sufficient clinical predictive power and will bridge the gap between proof-of-concept studies and a wider implementation within the oncology drug development for pathophysiological applications.

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The ketogenic diet is not effective in preclinical models of IDH1 wild-type and IDH1 mutant glioma

10.1101/2020.06.23.166652 ◽

2020 ◽

Author(s):

Rodrigo Javier ◽

Craig Horbinski

Keyword(s):

Clinical Trials ◽

Ketogenic Diet ◽

Sleeping Beauty ◽

Wild Type ◽

Preclinical Models ◽

Isocitrate Dehydrogenase 1 ◽

Low Carbohydrate ◽

Cellular Biochemistry

ABSTRACTInfiltrative gliomas are the most common neoplasms arising in the brain, and remain largely incurable despite decades of research. A subset of these gliomas contains mutations in isocitrate dehydrogenase 1 (IDH1mut). This mutation disrupts cellular biochemistry, and IDH1mut gliomas are generally less aggressive than IDH1 wild-type (IDH1wt) gliomas. Some preclinical studies and clinical trials have suggested that a ketogenic diet (KD), characterized by low-carbohydrate and high-fat content, may be beneficial in slowing glioma progression. However, not all studies have shown promising results, and to date, no study has addressed whether IDH1mut gliomas might be more sensitive to KD. The aim of the current study was to compare the effects of KD in preclinical models of IDH1wt versus IDH1mut gliomas. In vitro, simulating KD by treatment with the ketone body β-hydroxybutyrate had no effect on the proliferation of patient-derived IDH1wt or IDH1mut glioma cells. Likewise, KD had no effect on the in vivo growth of these patient-derived gliomas. Furthermore, mice engrafted with Sleeping-Beauty transposase-engineered IDH1wt and IDH1mut glioma showed no difference in survival while on KD. These data suggest that IDH1mut gliomas are not more responsive to KD, and that clinical trials further exploring KD in this subset of glioma patients may not be warranted.

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Sulfobetaine polymers for effective permeability into multicellular tumor spheroids (MCTSs)

Journal of Materials Chemistry B ◽

10.1039/d1tb02337c ◽

2022 ◽

Author(s):

Nobuyuki Morimoto ◽

Keisuke Ota ◽

Yuki Miura ◽

Heungsoo Shin ◽

Masaya Yamamoto

Keyword(s):

Drug Screening ◽

Effective Permeability ◽

Multicellular Tumor Spheroids ◽

Tumor Spheroids ◽

Tumor Tissues ◽

Animal Tests

Multicellular tumor spheroids (MCTSs) are attractive for drug screening before animal tests because they emulate an in vivo microenvironment. The permeability of the MCTSs and tumor tissues by the candidate...

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N-Truncated Aβ Starting at Position Four—Biochemical Features, Preclinical Models, and Potential as Drug Target in Alzheimer’s Disease

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2021.710579 ◽

2021 ◽

Vol 13 ◽

Author(s):

Thomas A. Bayer

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Clinical Trials ◽

Drug Target ◽

Passive Immunization ◽

Therapeutic Effects ◽

Preclinical Models ◽

Pyroglutamate Aβ

The discussion of whether amyloid plaque Aβ is a valid drug target to fight Alzheimer’s disease (AD) has been a matter of scientific dispute for decades. This question can only be settled by successful clinical trials and the approval of disease-modifying drugs. However, many clinical trials with antibodies against different regions of the amyloid Aβ peptide have been discontinued, as they did not meet the clinical endpoints required. Recently, passive immunization of AD patients with Donanemab, an antibody directed against the N-terminus of pyroglutamate Aβ, showed beneficial effects in a phase II trial, supporting the concept that N-truncated Aβ is a relevant target for AD therapy. There is long-standing evidence that N-truncated Aβ variants are the main variants found in amyloid plaques besides full-length Aβ1–42, t, therefore their role in triggering AD pathology and as targets for drug development are of interest. While the contribution of pyroglutamate Aβ3–42 to AD pathology has been well studied in the past, the potential role of Aβ4–42 has been largely neglected. The present review will therefore focus on Aβ4–42 as a possible drug target based on human and mouse pathology, in vitro and in vivo toxicity, and anti-Aβ4-X therapeutic effects in preclinical models.

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A Novel and Potent Inhibitor of E-Selectin, GMI-1687, Attenuates Thrombus Formation and Augments Chemotherapeutic Intervention of AML in Preclinical Models Following Subcutaneous Administration

Blood ◽

10.1182/blood-2018-99-116779 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4678-4678

Author(s):

John Peterson ◽

Myung-Gi Baek ◽

Silvia Locatelli-Hoops ◽

Ji-Won Lee ◽

Lingquan Deng ◽

...

Keyword(s):

Thrombus Formation ◽

Tumor Model ◽

Phase Iii ◽

Therapeutic Activity ◽

Preclinical Models ◽

Employment Equity ◽

Equity Ownership ◽

High Bioavailability

Abstract Uproleselan (GMI-1271), an E-selectin antagonist, has been shown in preclinical models to disrupt activation of cell survival pathways in acute myeloid leukemia (AML), enhance chemotherapy efficacy, and improve survival. Uproleselan received FDA breakthrough therapy designation for adult relapsed/refractory AML in 2017 and Phase III studies are ongoing. In the present studies we report on the in vitro and in vivo comparative activities of an innovative high potency E-selectin antagonist, GMI-1687, a potential subcutaneously administered follow-on drug candidate to Uproleselan. The binding constant, association and dissociation rates of GMI-1687 to immobilized recombinant human (rh) E-selectin were determined by surface plasmon resonance (SPR) at 25oC. The KD of GMI-1687 was 2.4 nM, with Kon = 3 x 106 M-1s-1 and Koff = 1 x10-2 s-1. Under similar experimental conditions the KD of Uproleselan was 520 nM with Kon = 0.02 x 106 M-1s-1 and Koff = 1 x10-2 s-1. GMI-1687 was evaluated for its ability to inhibit binding of sialyl Lea to immobilized rh E-selectin. The median IC50 (n=6 independent assays) of GMI-1687 and Uproleselan in this assay was 15 and 550 nM, respectively. The in vitro activity of GMI-1687 to release adherent KG1a AML cells from E-selectin coated wells was also determined. GMI-1687 at 100 nM detached approximately 55% of adherent AML cells and was significantly different from Uproleselan at an identical concentration (38% detachment, P=0.0216). The percent bioavailability (%F) of GMI-1687 was evaluated in male Sprague-Dawley rats following intravenous (IV) and subcutaneous (SC) routes of administration at 5 mg/kg. The mean (+/- SD) SC %F for GMI-1687 was 126 +/- 3.8%. GMI-1687 also showed high bioavailability in CD-1 mice after SC administration of 0.58 mg/kg with %F = 132 +/-38. The in vivo therapeutic activity of GMI-1687 following SC administration was assessed in an acute model of inferior vena cava (IVC) thrombosis and a tumor model of AML.Immediately following the induction of a non-occlusive thrombosis via electrical stimulation (250 mAmp) of the IVC, cohorts of male C57BL/6J mice (n=5/group) were given a single SC injection of saline (0.1 mL); Uproleselan (40 mg/kg); or GMI-1687 (4 mg/kg, 0.4 mg/kg or 0.04 mg/kg), and twenty-four hrs post thrombus induction the IVC was harvested from all mice and thrombus weights were determined. Treatment with GMI-1687 decreased thrombus formation with significant inhibition at 0.04 mg/kg (92%, P<0.001 compared to saline control). The inhibition of thrombus formation with GMI-1687 dosed at 0.04 mg/kg was statistically indistinguishable from Uproleselan administered SC at 40 mg/kg (97% inhibition). The therapeutic activity of SC GMI-1687 was also observed in combination with chemotherapy in a U937 tumor model. Three days post IV injection of U937 tumor cells, bone marrow ablated, female NOD/SCID mice (n=10/group) were treated with saline (0.1 mL SC QDx14); GMI-1687 (0.04 mg/kg SC QDx14) alone; cytarabine (AraC 300 mg/kg IP QDx3) + daunorubicin (DNR 3 mg/kg IV QDx1), or the combination of GMI-1687 and AraC + DNR. All treatments were well tolerated. The median survival time (MST) of mice treated with AraC + DNR was 36 days and statistically different (P<0.001) to groups treated with saline (MST=22 days) or GMI-1687 alone (MST=23 days). Importantly, the therapeutic activity of AraC+DNR was significantly enhanced when combined with GMI-1687 (MST>47.5 days, P=0.0153 compared to AraC+DNR alone). In summary, a highly potent innovative antagonist of E-selectin, GMI-1687, has been produced that demonstrates high bioavailability following SC administration. SC injection of GMI-1687 shows significant activity in preclinical models previously reported for parenteral administration of Uproleselan, but at approximately 250-fold lower dose. GMI-1687 is therefore well-positioned for potential use in outpatient treatment settings where an E-selectin antagonist has therapeutic relevance. IND-enabling studies with GMI-1687 are currently underway. Disclosures Peterson: GlycoMimetics: Employment, Equity Ownership. Baek:GlycoMimetics: Employment, Equity Ownership. Locatelli-Hoops:GlycoMimetics: Employment, Equity Ownership. Lee:GlycoMimetics: Employment, Equity Ownership. Deng:GlycoMimetics: Employment, Equity Ownership. Stewart:GlycoMimetics: Employment, Equity Ownership. Smith:GlycoMimetics: Employment, Equity Ownership. Fogler:GlycoMimetics: Employment, Equity Ownership. Magnani:GlycoMimetics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

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The effects of palbociclib in combination with radiation in preclinical models of aggressive meningioma

Neuro-Oncology Advances ◽

10.1093/noajnl/vdab085 ◽

2021 ◽

Author(s):

Craig Horbinski ◽

Guifa Xi ◽

Yufen Wang ◽

Rintaro Hashizume ◽

Mahesh Gopalakrishnan ◽

...

Keyword(s):

Clinical Trial ◽

Cell Viability ◽

Therapeutic Potential ◽

The Body ◽

Preclinical Models ◽

Cyclin Dependent Kinases ◽

Tumor Tissues ◽

The Brain

Abstract Background Meningiomas are the most common tumor arising within the cranium of adults. Despite surgical resection and radiotherapy, many meningiomas invade the brain, and many recur, often repeatedly. To date, no chemotherapy has proven effective against such tumors. Thus, there is an urgent need for chemotherapeutic options for treating meningiomas, especially those that enhance radiotherapy. Palbociclib is an inhibitor of cyclin-dependent kinases 4 and 6 that has been shown to enhance radiotherapy in preclinical models of other cancers, is well-tolerated in patients, and is used to treat malignancies elsewhere in the body. We therefore sought to determine its therapeutic potential in preclinical models of meningioma. Methods Patient-derived meningioma cells were tested in vitro and in vivo with combinations of palbociclib and radiation. Outputs included cell viability, apoptosis, clonogenicity, engrafted mouse survival, and analysis of engrafted tumor tissues after therapy. Results We found that palbociclib was highly potent against p16-deficient, Rb-intact CH157 and IOMM-Lee meningioma cells in vitro, but was ineffective against p16-intact, Rb-deficient SF8295 meningioma cells. Palbociclib also enhanced the in vitro efficacy of radiotherapy when used against p16-deficient meningioma, as indicated by cell viability and clonogenic assays. In vivo, the combination of palbociclib and radiation extended the survival of mice bearing orthotopic p16 deficient meningioma xenografts, relative to each as a monotherapy. Conclusions These data suggest that palbociclib could be repurposed to treat patients with p16-deficient, Rb-intact meningiomas, and that a clinical trial in combination with radiation therapy merits consideration.

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Perspectives in breast and ovarian cancer chemotherapy by nanomedicine approach: nanoformulations in clinical research

Current Medicinal Chemistry ◽

10.2174/0929867327666200819115403 ◽

2020 ◽

Vol 27 ◽

Cited By ~ 1

Author(s):

Cristina Martín-Sabroso ◽

Ana Isabel Fraguas-Sánchez ◽

Rafaela Raposo-González ◽

Ana Isabel TorresSuárez

Keyword(s):

Ovarian Cancer ◽

Clinical Trials ◽

Clinical Research ◽

Maximum Tolerated Dose ◽

Production Costs ◽

Phase Iii ◽

Ovarian Carcinomas ◽

Good Tool

: Breast and ovarian carcinomas represent major health problems in women worldwide. Chemotherapy constitutes a main treatment strategy, and the use of nanocarriers a good tool to improve it. Several nanoformulations have already been approved, and others are under clinical trials for the treatment of both types of cancers. Objective: This review focuses on the analysis of the nanoformulations that are under clinical research in the treatment of these neoplasms. Results: Currently, there are 6 nanoformulations in clinical trials for breast and ovarian carcinomas, most of them in phase II and phase III. In the case of breast cancer treatment, these nanomedicines contain paclitaxel; and, for ovarian cancer, nanoformulations containing paclitaxel or camptothecin analogs are being evaluated. The nanoencapsulation of these antineoplastics facilitates their administration and reduces their systemic toxicity. Nevertheless, the final approval and commercialization of nanoformulations may be limited by other aspects like lack of correlation between the efficacy results evaluated at in vitro and in vivo levels, difficulty in producing large batches of nanoformulations in a reproducible manner and high production costs compared to conventional formulations of antineoplastics. However, these challenges are not insurmountable and the number of approved nanoformulations for cancer therapy is growing. Conclusion: Reviewed nanoformulations have shown, in general, excellent results, demonstrating a good safety profile, a higher maximum tolerated dose and a similar or even slightly better antitumor efficacy compared to the administration of free drugs, reinforcing the use of nano-chemotherapy in both breast and ovarian tumors.

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Further Considerations Towards an Effective and Efficient Oncology Drug Discovery DMPK Strategy

Current Drug Metabolism ◽

10.2174/1389200221666200312104837 ◽

2020 ◽

Vol 21 (2) ◽

pp. 145-162 ◽

Cited By ~ 1

Author(s):

Beth Williamson ◽

Nicola Colclough ◽

Adrian John Fretland ◽

Barry Christopher Jones ◽

Rhys Dafydd Owen Jones ◽

...

Keyword(s):

Drug Discovery ◽

Drug Exposure ◽

Phase Iii ◽

Human Pharmacokinetics ◽

Vitro Assay ◽

Pharmacodynamic Modelling ◽

Oncology Drug ◽

The Impact

Background: DMPK data and knowledge are critical in maximising the probability of developing successful drugs via the application of in silico, in vitro and in vivo approaches in drug discovery. Methods: The evaluation, optimisation and prediction of human pharmacokinetics is now a mainstay within drug discovery. These elements are at the heart of the ‘right tissue’ component of AstraZeneca’s ‘5Rs framework’ which, since its adoption, has resulted in increased success of Phase III clinical trials. With the plethora of DMPK related assays and models available, there is a need to continually refine and improve the effectiveness and efficiency of approaches best to facilitate the progression of quality compounds for human clinical testing. Results: This article builds on previously published strategies from our laboratories, highlighting recent discoveries and successes, that brings our AstraZeneca Oncology DMPK strategy up to date. We review the core aspects of DMPK in Oncology drug discovery and highlight data recently generated in our laboratories that have influenced our screening cascade and experimental design. We present data and our experiences of employing cassette animal PK, as well as re-evaluating in vitro assay design for metabolic stability assessments and expanding our use of freshly excised animal and human tissue to best inform first time in human dosing and dose escalation studies. Conclusion: Application of our updated drug-drug interaction and central nervous system drug exposure strategies are exemplified, as is the impact of physiologically based pharmacokinetic and pharmacokinetic-pharmacodynamic modelling for human predictions.

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Mouse Models in Prostate Cancer Translational Research: From Xenograft to PDX

BioMed Research International ◽

10.1155/2016/9750795 ◽

2016 ◽

Vol 2016 ◽

pp. 1-11 ◽

Cited By ~ 25

Author(s):

Domenica Rea ◽

Vitale del Vecchio ◽

Giuseppe Palma ◽

Antonio Barbieri ◽

Michela Falco ◽

...

Keyword(s):

Mouse Models ◽

Disease Incidence ◽

Receptor Expression ◽

Differential Sensitivity ◽

Phase Iii ◽

Preclinical Models ◽

Preclinical Research ◽

Advantages And Disadvantages

Despite the advancement of clinical and preclinical research on PCa, which resulted in the last five years in a decrement of disease incidence by 3-4%, it remains the most frequent cancer in men and the second for mortality rate. Based on this evidence we present a brief dissertation on numerous preclinical models, comparing their advantages and disadvantages; among this we report the PDX mouse models that show greater fidelity to the disease, in terms of histopathologic features of implanted tumor, gene and miRNA expression, and metastatic pattern, well describing all tumor progression stages; this characteristic encourages the translation of preclinical results. These models become particularly useful in meeting the need of new treatments identification that eradicate PCa bone metastases growing, clarifying pathway of angiogenesis, identifying castration-resistant stem-like cells, and studying the antiandrogen therapies. Also of considerable interest are the studies of 3D cell cultures derived from PDX, which have the ability to maintain PDX cell viability with continued native androgen receptor expression, also showing a differential sensitivity to drugs. 3D PDX PCa may represent a diagnostic platform for the rapid assessment of drugs and push personalized medicine. Today the development of preclinical models in vitro and in vivo is necessary in order to obtain increasingly reliable answers before reaching phase III of the drug discovery.

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