Researchers identify key factors impacting adaptive therapy
Spatial organization and competition between drug-resistant cells affect treatment outcomes

Date:
May 9, 2022
Source:
H. Lee Moffitt Cancer Center & Research Institute
Summary:
Researchers have been investigating an alternative treatment
approach called adaptive therapy that focuses on maintaining disease
control instead of complete tumor cell elimination. Researchers
used mathematical modeling to reveal that the spatial organization
of a tumor is an important factor that governs how cells compete
with one another and the effectiveness of adaptive therapy.



FULL STORY ==========================================================================
Most cancer treatments are based on using the maximum tolerated dose
of a drug to kill as many cancer cells as possible. While this approach
has led to patients achieving good responses to therapy, most patients
develop drug resistance and disease recurrence. Researchers in the Center
of Excellence for Evolutionary Therapy at Moffitt Cancer Center have been investigating an alternative treatment approach called adaptive therapy
that focuses on maintaining disease control instead of complete tumor
cell elimination. In a new study published in Communications Medicine,
the researchers used mathematical modeling to reveal that the spatial organization of a tumor is an important factor that governs how cells
compete with one another and the effectiveness of adaptive therapy.


==========================================================================
The development of drug resistance is one of the primary concerns in the oncology field. As each new targeted therapy is added to the arsenal of potential therapeutics, scientists are already addressing how to tackle inevitable drug resistance that occurs through a variety of different mechanisms. Drug resistance is common when using a maximum tolerated dose
of a drug because this approach provides a growth advantage to existing resistant cells as they become free from competition with sensitive cells.

Alternatively, the emerging concept of adaptive therapy is based on
ecological principles that predict that maintaining a population of
cancer cells that is sensitive to therapies will keep the development
of resistance in check through competition. Similar approaches are used
in other biological situations, such as insecticide use. It is now well accepted that using a less aggressive spraying approach and maintaining
a "refuge" insecticide-free spot allows insecticide-sensitive insects
to breed with resistant populations, which limits the propagation of
resistant groups.

These ecological concepts are now being more fully investigated in cancer.

Promising results were observed from a recent early-stage clinical trial
of prostate cancer patients treated with adaptive therapy, and additional larger clinical studies of adaptive therapy are underway in prostate
cancer and melanoma. While these investigations continue, scientists
need to improve their understanding of the cellular interactions that
impact adaptive therapy.

Previous studies have revealed that adaptive therapy depends on the
competitive interactions of sensitive and resistance cells within a
spatially constrained tumor; however, it is unknown how competition occurs
and how it is impacted by the spatial arrangement of cells within the
tumor. Rather than using typical cell or mouse models to study adaptive therapy, the Moffitt research team is using mathematical modeling that can better incorporate the numerous variables that impact adaptive therapy.

In their study, the researchers used a two-dimensional model of a tumor composed of drug sensitive and resistant cells to directly quantify how different cells compete for space.

"While competition is thought to be the driving mechanism behind adaptive therapy, it is challenging to assert its role in real tumors. This is
because it is difficult to rule out confounding factors, such as treatment induced changes in the tumor vasculature or the immune response,"
said Maximilian Strobl, Ph.D., a postdoctoral researcher at Moffitt and
first author of the study. "However, in our computational model we can
control and monitor the cells in a way not possible in the wet lab. We
seized this opportunity to explicitly measure how often a resistant cell
is blocked from division during adaptive therapy. The results of these experiments were surprising." Currently, it is believed that adaptive
therapy permits drug sensitive cells to keep resistant cells in check
through competition, but the Moffitt team discovered that competition
between resistant cells themselves and their distribution across a tumor
are important factors that also impact adaptive therapy. The researchers
showed that adaptive therapy will be most effective when resistant cells
are clustered in a single area and surrounded by sensitive cells. This
scenario will allow resistant cells to be kept in check by sensitive
cells and other resistant cells.

These results suggest that it will be important to understand how
resistant cells are spatially organized to determine the appropriate
adaptive therapy treatment schedule; however, determining cell
resistance patterns may require tissue biopsies that would be invasive
and impractical. As an alternative approach, the researchers used
response data from prostate cancer patients undergoing adaptive therapy
to demonstrate that it may be possible to use mathematical modeling
to determine spatial organization patterns. Patients who cycled through
therapy quickly had more diffuse tumors, while patients who cycled through therapy more slowly tended to have more compact tumors that may be better suited to adaptive therapy.

While additional studies are needed to more fully understand adaptive
therapy, these results provide new insights into factors that are critical
in determining its success.

"We have shown that the spatial organization of resistant populations
is an important and understudied factor in cancer treatment. This
strengthens the argument for patient-specific, adaptive therapy
protocols that explicitly consider not only a tumor's evolution but
also its ecology," said Sandy Anderson, Ph.D., director of the Center
of Excellence for Evolutionary Therapy and chair of the Department of Integrated Mathematical Oncology.

This work was supported by the Engineering and Physical Sciences Research Council and the Medical Research Council (EP/L016044/1), the National
Cancer Institute (U01CA232382 and U54CA193489) and the Moffitt Center
of Excellence for Evolutionary Therapy.


========================================================================== Story Source: Materials provided by H._Lee_Moffitt_Cancer_Center_&_Research_Institute. Note: Content may be
edited for style and length.


========================================================================== Journal Reference:
1. Maximilian A. R. Strobl, Jill Gallaher, Jeffrey West, Mark
Robertson-
Tessi, Philip K. Maini, Alexander R. A. Anderson. Spatial structure
impacts adaptive therapy by shaping intra-tumoral competition.

Communications Medicine, 2022; 2 (1) DOI: 10.1038/s43856-022-00110-x ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/05/220509162805.htm

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