Adaptive therapy borrows from nature to keep rhabdomyosarcoma in check
“During the whole course of treatment – I’m sure like many other parents – apart from relying on Damon and his treatment expertise to try to determine the best treatment options, I was reading everything under the sun to try to get a working knowledge of what Theo was up against, what his treatment and clinical trial options were, and what was the state of the science,” Mr. Huff says.
Unfortunately, the characteristics of Theo’s disease, including his very young age at onset and diagnosis of stage 4 metastatic disease, conspired against him, and despite undergoing 14 months of chemotherapy, Theo died of the disease in October 2016, 5 months shy of what would have been his second birthday.
In their grief, Mr. Huff, a real estate lawyer with a practice in Clearwater, Fla., and his wife, Leah, were determined to help other families of children with cancer and settled on the National Pediatric Cancer Foundation. Mr. Huff joined the board of directors of the foundation, which is collaborating with Moffitt Cancer Center on the adaptive therapy trial.
An evolutionary primer (cancer edition)
To get a better idea of just how adaptive therapy works, it is helpful to view cancer cells through the lens of species development, adaptation, extinction, and evolution.
“Cancer cells compete against each other in a dynamic environment. Their tumor ecosystems exhibit spatial and temporal fluctuations in blood-borne nutrients, oxygen, growth factors, immune cells, and hormones,” Dr. Reed and colleagues wrote.
These influences can affect genetically identical cancer cells, which may begin to diverge from one another depending on their location in a tumor and the availability of nutrients, which in turn can result in two once-identical cells exhibiting different transcription rates for growth factors.
“Ultimately, this may affect the rate of progression through the cell cycle, leading to distinct rates of proliferation and mutational acquisition,” they wrote.
The diverging subpopulations will begin to develop different methods for adapting to the tumor microenvironment, with unique strategies for both accelerating growth and avoiding hazards such as chemotherapy drugs or radiation, the investigators explained.
“By the time a cancer becomes clinically apparent, cancer cells have transformed from a single clone into a diverse community of cell types evolving in response to a spatially and temporally heterogeneous tumor environment. Theoretically, a 10-gram cancer may contain the same order of magnitude of cancer cells as there are humans on earth, with tremendous diversity of phenotypes and environments,” they wrote.
Survival of the fittest
The competition of individuals within and between species described by Darwin also applies to cancer cells, in their interactions both with each other and with stromal cells and immune cells resulting in “the progressive replacement of less fit phenotypes by those that are more fit,” Dr. Reed and colleagues explained.
And just like the old joke about two hikers trying to escape from a charging grizzly bear (one says, “This is futile – we can’t outrun a grizzly,” and the other says, “I only have to outrun you!”), cancer cells only need to be more resistant to therapeutic attack than normal cells that are critical to function.
“This may explain why initial responses in certain solid tumors (notably rhabdomyosarcoma) do not predict eventual survival. The sensitivities of the dominant cancer cell populations dictate the initial response, but it is the ecology and evolution of the rare and more resistant populations that determine cure or relapse,” they wrote.
