Create 3D multiple myeloma model to aid preclinical development efforts

Multiple myeloma is an incurable cancer of the bone marrow; most patients develop resistance against first line therapy Velcade (bortezomib) sooner or later, which is a problem because few alternative drugs are available.

Part of the reason for this is that to date there have been no screening systems to allow scientists to study the effects of multiple myeloma drug candidates in a 3-D environment.

This may soon change according to European scientists who have grown miniature human myelomas in chicken eggs in a microenviroment that includes extracellular matrix compounds (ECM) and supportive stromal cells.

3D multiple myeloma model

3D Multiple Myeloma Model

“We wanted to generate a natural microenviroment by combining 3-D co-culture in ECM matrix with in vivo growth conditions in chicken embryos,” said Gerold Untergasser at Innsbruck Medical University in Austria.

“The previous standard 2 D culture was not very successful for testing drugs on myeloma cells, because some drugs were not very efficient in co-culture conditions, due to the supportive function of stromal cells.”

Trial assays have been successful according to Untergasser, who said novel marine compounds synthesized by Spanish API firm Pharmamar “displayed a strong anti-myeloma and anti-angiogenic activity,” Untergasser said.

Tumours in eggs

The scientists approach is to cultivate tumour cells with human mensenchymal cells from the bone marrow and collagen in the shape of 3-D cell spheres, simulating tumours in bone marrow.

After removing the eggshells, the researchers transfer the cell spheres to the outer chorioallantoic membrane. This membrane provides a perfect base for growing miniature human tumours in a petri dish. It allows putative drugs to be added to see if they can kill myeloma cells.

This is not straightforward because the mensenchymal cells protect the tumor in the test system just as they do in patients. Cancer drugs have to overcome this protective shield.

“We tested already tested four different human myeloma clones and work on refining of the system by including bone-replacement material based on hydroxyapatite (calcium apatite) to provide an optimal substrate for myeloma cell growth of bone marrow aspirates of patients,” Untergasser explained.

The spheroids have a diameter of about 2 mm and their generation takes just 1 to 2 hrs. The preparation of eggs takes about one week before grafting of spheroids.

The group is working to improve the system for patients by constructing spheroids that more resemble the natural microenviroment of the human bone.

Asked what benefits this technique offers, Untergasser said it makes large-scale screening of compounds more feasible, offers easy handling and imaging of tumours and is less costly than immunocompromised mice that require special facilities.

Also the embryonic tissue of the chorioallantoic membrane of chicken is a perfect substrate for growth of myeloma cells, because is strongly vascularized and full of supportive growth factors.

The technique was developed as part of an EU project called OPTATIO and a video publication was released in the Journal of Visualized Experiments. The video is entitled “Establishment of a Human Multiple Myeloma Xenograft Model in the Chicken to Study Tumor Growth, Invasion and Angiogenesis.”

Preclinical and clinical stages of drug development

Medicilon hosted a Preclinical Development of Innovative Drugs Summit

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In the process of preclinical testing of a compound or biological agent into a drug, the compound involved must go through the testing phase. First, we need to identify potential targets that can treat the disease. Then, a variety of compounds or preparations are screened out. Any compound that has shown potential as a drug for the treatment of this disease needs to be tested for toxicity before clinical testing to reduce the possibility of injury. preclinical testing What is the basis of preclinical testing? According to US Food and Drug Administration (FDA) regulations, a series of tests are required before a new drug is approved for use. In the first stage, basic research determines a hypothetical target for the treatment of a certain disease, and then screens small molecules or biological compounds to discover any substance with the potential to treat the disease. Then, a preclinical research phase followed, before which, as described above, the potential toxicity of the compou

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Inventory of the three major in vitro pharmacokinetic research methods

The metabolic properties of a compound are an essential factor in whether or not it can be used as a drug in the clinical setting, so pharmacokinetic studies of newly synthesized compounds are required in drug development. In vitro incubation with liver microsomes, recombinant CYP450 enzyme lines, and in vitro incubation with hepatocytes are some of the more common in vitro drug metabolism methods. 1. In vitro incubation method with liver microsomes The metabolic stability and metabolic phenotypes of candidate compounds in different species of liver microsomes are good predictors of the metabolic properties of compounds in vivo. They are practical tools for evaluating candidate compounds in the pre-development phase of drug development. Liver microsomes include rat liver microsomes, human liver microsomes, canine liver microsomes, monkey liver microsomes, and mouse liver microsomes. In in vitro incubation of the liver, microsomes are the "gold standard" for in vitro d

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Novel Parkinson’s Therapies Possible with New Mouse Model

Parkinson's disease (PD) is a neurodegenerative disorder that is marked by the accumulation of the protein, α-synuclein (αS), into clumps known as Lewy bodies, which diminish neural health. Now, researchers from Brigham and Women's Hospital (BWH) report the development of a mouse model to induce PD-like αS aggregation, leading to resting tremor and abnormal movement control. The mouse responds to L-DOPA, similarly to patients with PD. The team's study (“Abrogating Native α-Synuclein Tetramers in Mice Causes a L-DOPA-Responsive Motor Syndrome Closely Resembling Parkinson’s Disease”) on the use of this transgenic mouse model appears in Neuron . “α-Synuclein (αS) regulates vesicle exocytosis but forms insoluble deposits in PD. Developing disease-modifying therapies requires animal models that reproduce cardinal features of PD. We recently described a previously unrecognized physiological form of αS, α-helical tetramers, and showed that familial PD-causing missense mutati

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