Researchers use single-cell imaging and mathematical modeling to determine effective drug properties

March 13, 2018, H. Lee Moffitt Cancer Center & Research Institute
Credit: Susan Buck Ms/Public Domain

Drug therapies that target a specific molecule have changed the way patients are treated for cancer and greatly improved survival rates. However, some patients do not respond to these therapies because the drug is not reaching the tumor cells effectively. In a new study published in Scientific Reports, Moffitt Cancer Center researchers combined single-cell imaging of cancer cells in mice with mathematical modeling to determine which drug characteristics are the most important for efficient drug uptake.

One of the inherent problems with targeted therapies is that tumors and their surrounding environment are complex and heterogeneous. Not all cells in a given tumor are alike. They can differ from one another in the expression of the targeted membrane receptors which may result in inadequate uptake and non-uniform response to the targeting drug. Additionally, the surrounding tumor environment is composed of different cell types with different properties and densities that can impact the ability of a drug to be effective.

These variations make it difficult to develop drugs that can effectively target all of the cells in a tumor. Furthermore, these cellular and genetic differences may cause a patient to be unresponsive to a cancer-targeted drug because some tumor cells may not be fully exposed to the drug and this incomplete exposure may enable these cells to develop drug resistance.

"Clinical success or failure of targeted therapy depends heavily on whether the drug molecules are able to reach all tumor cells and engage with their molecular targets to invoke the desired therapeutic effect," said Kasia A. Rejniak, Ph.D., associate member of the Department of Integrated Mathematical Oncology at Moffitt. This work was accomplished through collaboration between Rejniak computational group and the laboratory group of Dave L. Morse, Ph.D., associate member of the Department of Cancer Physiology.

The standard methods that scientists use to study drug uptake are based on the idea that a tumor and its surroundings have uniform characteristics. However, this assumption is inaccurate and may lead to a one-size-fits-all approach to treatment. The Moffitt research team wanted to take a different approach to study drug uptake. They used mathematical modeling and imaging techniques that allowed them to track and predict the ability of a single cell to take up a drug. Within their model, they compared different drug characteristics and tumor properties to determine which conditions lead to more effective drug uptake by a cell.

They discovered that the amount of drug that binds to a cell is dependent on how quickly a drug diffused through the tissue rather than on the concentration of drug that enters the tissue. Drugs that diffused quickly tended to bind more effectively to cells that were further away from blood vessels. Alternatively, drugs that diffused slowly tended to bind to cells that were closer to blood vessels and were more effective when the cells were tightly packed. The researchers also showed that drugs that are released quickly are able to bind more effectively to cells with different levels of drug receptors.

These discoveries suggest that changing different properties of a drug or the way a is administered may lead to increased delivery to . "For example, to treat the fast-growing cells located near the vasculature, slowly diffusing agents may be beneficial. In contrast, for the dormant in poorly vascularized regions, the highly mobile agents may be preferential, or in some cancers, local injection directly to the site may be beneficial," explained Rejniak. Ultimately, the researchers hope that their approach could eventually be used to design more personalized treatment options for patients.

Explore further: Researchers discover new approach to stimulate an immune response against tumor cells

More information: Aleksandra Karolak et al, Targeting Ligand Specificity Linked to Tumor Tissue Topological Heterogeneity via Single-Cell Micro-Pharmacological Modeling, Scientific Reports (2018). DOI: 10.1038/s41598-018-21883-z

Related Stories

Researchers discover new approach to stimulate an immune response against tumor cells

January 30, 2018
New drugs that activate the immune system to target cancer cells have improved the lives of many patients with cancer. However, immunotherapies are not effective in all patients, and the success of these therapies depends ...

Two drugs are better than one in fight against leukaemia

March 8, 2018
Adelaide scientists have devised a way to enhance the effectiveness of a patient's leukaemia treatment by using a combination of drugs.

Team develops technology to find optimum drug target for cancer

December 18, 2017
A KAIST research team led by Professor Kwang-Hyun Cho of the Department of Bio and Brain Engineering developed technology to find the optimum drug targets for specific types of cancer cells. The team used systems biology ...

Team discovers opportunities to overcome cancer treatment resistance

April 27, 2017
A collaborative Cleveland Clinic, University of Oxford and Moffitt Cancer Center team of researchers has proven the theory that, while resistance to targeted treatment in cancer is truly a moving target, there are opportunities ...

Researchers discover mechanism leading to BRAF inhibitor resistance in melanoma

June 19, 2015
The development of targeted therapies has significantly improved the survival of melanoma patients over the last decade; however, patients often relapse because many therapies do not kill all of the tumor cells, and the remaining ...

Recommended for you

Researchers suggest new treatment for rare inherited cancers

July 16, 2018
Studying two rare inherited cancer syndromes, Yale Cancer Center (YCC) scientists have found the cancers are driven by a breakdown in how cells repair their DNA. The discovery, published today in Nature Genetics, suggests ...

Researchers map 'family trees' of acute myeloid leukemia

July 16, 2018
For the first time, a team of international researchers has mapped the family trees of cancer cells in acute myeloid leukaemia (AML) to understand how this blood cancer responds to a new drug, enasidenib. The work also explains ...

Scientists sharpen the edges of cancer chemotherapy with CRISPR

July 13, 2018
Tackling unsolved problems is a cornerstone of scientific research, propelled by the power and promise of new technologies. Indeed, one of the shiniest tools in the biomedical toolkit these days is the genome editing system ...

Products of omega-3 fatty acid metabolism may have anticancer effects, study shows

July 13, 2018
A class of molecules formed when the body metabolizes omega-3 fatty acids could inhibit cancer's growth and spread, University of Illinois researchers report in a new study in mice. The molecules, called endocannabinoids, ...

Looking at the urine and blood may be best in diagnosing myeloma

July 13, 2018
When it comes to diagnosing a condition in which the plasma cells that normally make antibodies to protect us instead become cancerous, it may be better to look at the urine as well as the serum of our blood for answers, ...

Massive genome havoc in breast cancer is revealed

July 12, 2018
In cancer cells, genetic errors wreak havoc. Misspelled genes, as well as structural variations—larger-scale rearrangements of DNA that can encompass large chunks of chromosomes—disturb carefully balanced mechanisms that ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.