Mathematical modeling offers new way to understand variable responses to targeted therapy

April 3, 2018, H. Lee Moffitt Cancer Center & Research Institute
Cancer cell during cell division. Credit: National Institutes of Health

Cancer therapies that target a specific protein have improved outcomes for patients. However, many patients eventually develop resistance to these targeted therapies and their cancer comes back. It is believed that differences among tumor cells, or heterogeneity, may contribute to this drug resistance. Moffitt Cancer Center researchers are using a unique approach by combining typical cell culture studies with mathematical modeling to determine how heterogeneity within a tumor and the surrounding tumor environment affect responses to targeted drug therapies. Their study was published online in PLOS Biology.

Cells within a single can be very different. They may have different genetic characteristics leading to different protein levels or activity, and act differently in response to a stimulus or targeted . Additionally, the surrounding tumor environment can produce chemical signals that further alter and their response to targeted therapies.

The typical approach that researchers use to study development and treatment is to consider the within a given tumor to be the same and to have a similar response to therapy. However, this assumption is not what actually occurs and tends to limit the design of effective cancer therapies. By using mathematical modeling and experimental data, Moffitt researchers are able to take tumor cell heterogeneity into consideration. This allows more accurate prediction of how cells would respond to targeted cancer therapy and suggests more effective ones.

The interdisciplinary research team was composed of mathematical modelers, led by Alexander Anderson, Ph.D., chair of the Department of Integrated Mathematical Oncology at Moffitt, and basic/translational biologists, led by Eric Haura, M.D., co-leader of the Chemical Biology & Molecular Medicine Program and senior member of the Department of Thoracic Oncology at Moffitt. Together, they created a mathematical model based on their experimental data from a lung cancer cell line. There are many signaling pathways known to be involved in cancer progression. The researchers decided to focus on two key pathways, the RAS-MAPK and the AKT-PI3K signaling pathways that are commonly deregulated in many different types of cancer. They performed cell culture experiments in the presence and absence of a protein called HGF produced by cells in the surrounding tumor environment. HGF is known to contribute to resistance. They also treated the with different inhibitors to determine how cells respond to these targeted drugs. They used this data to create mathematical models that made new predictions and then confirmed these predictions back in the lung cancer cell line.

The combined results show that cancer cells have different responses to targeted drug therapies because of different protein activities. Also, some cells may not respond to a targeted inhibitor because alternative signaling pathways may become activated and bypass that inhibitor. As a result, it may be necessary to use a combination of drug inhibitors to target as many of the diverse tumor cells as possible. The researchers used their model to show certain drug combinations are more effective at reducing cell viability. However, they also demonstrated that the surrounding tumor environment could alter a cell to a drug or drug combination.

Importantly, the researchers demonstrated that all of these variations in cell responses to drug inhibitors and the tumor environment could cause certain cells within a population to become dominant, leading to . Furthermore, certain drug inhibitors and combinations can produce relatively more tumor cell heterogeneity post-treatment.

A major advantage of this mathematical approach is that it can analyze many different tumor scenarios and drug combinations, and offers a way to more accurately predict heterogeneous tumor responses. "We are only just beginning to understand the importance of non-genetic heterogeneity. Much more needs to be done in teasing apart the contributions of genetics, cells, and the microenvironment; how they interact and modulate one another, and how this might alter our current combination treatment strategies," explained lead study authors Eunjung Kim, Ph.D and Alexander Anderson, Ph.D. of the Department of Integrated Mathematical Oncology at Moffitt.

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

More information: Eunjung Kim et al, Cell signaling heterogeneity is modulated by both cell-intrinsic and -extrinsic mechanisms: An integrated approach to understanding targeted therapy, PLOS Biology (2018). DOI: 10.1371/journal.pbio.2002930

Related Stories

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

March 13, 2018
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 ...

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 ...

Researchers predict melanoma responses through mathematical modeling

November 10, 2016
Scientists have significantly improved their understanding of cancer and have developed numerous therapies that have helped to reduce patient mortality; however, the majority of drugs that make it to the clinical trial phase ...

Differences in tumor cell metabolism affect growth, invasion and response

May 19, 2015
Cells within a tumor are not the same; they may have different genetic mutations and different characteristics during growth and throughout treatment. These differences make treating tumors extremely difficult and often lead ...

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 ...

Fibroblasts contribute to melanoma tumor growth: study

January 5, 2012
Fibroblasts, cells that play a role in the structural framework of tissues, play an apparent role in melanoma tumor growth. Fibroblasts also contribute to melanoma drug resistance and may also facilitate the "flare" response ...

Recommended for you

Single-cell study in a childhood brain tumor affirms the importance of context

April 20, 2018
In defining the cellular context of diffuse midline gliomas, researchers find the cells fueling their growth and suggest a potential approach to treating them: forcing their cells to be more mature.

Aggressive breast cancer already has resistant tumour cells prior to chemotherapy

April 20, 2018
Difficult to treat and aggressive "triple-negative" breast cancer is chemoresistant even before chemotherapy begins, a new study by researchers from Karolinska Institutet and the University of Texas MD Anderson Cancer Center ...

Mechanism that drives development of liver cancer brought on by non-alcoholic fatty liver disease discovered

April 19, 2018
A team of researchers from several institutions in China has found a mechanism that appears to drive the development of a type of liver cancer not caused by alcohol consumption. In their paper published in the journal Science ...

Discovery adds to evidence that some children are predisposed to develop leukemia

April 19, 2018
St. Jude Children's Research Hospital researchers have made a discovery that expands the list of genes to include when screening individuals for possible increased susceptibility to childhood leukemia. The finding is reported ...

Scientists identify 170 potential lung cancer drug targets using unique cellular library

April 19, 2018
After testing more than 200,000 chemical compounds, UT Southwestern's Simmons Cancer Center researchers have identified 170 chemicals that are potential candidates for development into drug therapies for lung cancer.

Chip-based blood test for multiple myeloma could make bone biopsies a relic of the past

April 19, 2018
The diagnosis and treatment of multiple myeloma, a cancer affecting plasma cells, traditionally forces patients to suffer through a painful bone biopsy. During that procedure, doctors insert a bone-biopsy needle through an ...

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.