TAMPA, Fla. (Sept. 17, 2012) Robert A. Gatenby, M.D., senior member of Moffitt Cancer Center's Department of Diagnostic Imaging and Integrated Mathematical Oncology, and his colleagues have received a four-year, $2.1 million grant from the National Cancer Institute to carry out pre-clinical research focused on cancer cell drug resistance. Researchers will examine cancer's evolutionary mechanisms of drug resistance and focus on prevention strategies.
The grant (CA170595-01) stems from the NCI's "Provocative Questions" Project. Researchers from across the country were asked to respond to 24 provocative questions in hopes of stimulating the NCI's research communities. The questions focused on specific advances in understanding cancer and cancer control, broad issues on the biology of cancer, the likelihood of progress in less than a decade, and ways to overcome obstacles to achieving long-term goals.
Gatenby answered question 21: "Given the appearance of resistance in response to cell killing therapies, can we extend survival by using approaches that keep tumors static?"
According to the NCI, the question addresses the relationship between drug resistance in cancer treatment and the Darwinian Theory about natural selection and adaptation to selective environmental pressures. In the case of cancer cells, the environmental pressure refers to chemotherapy and survival means becoming resistant to the drugs aimed at killing them.
The question also asks whether an evolutionary approach can create a balance in tumor cells by not creating resistance through attempts to kill cells but, rather, provide an environment where selection forces are weak. Speculation is that under weak selective forces, cancer cells can live in a form of balance, not dying or becoming drug resistant.
Gatenby's approach to treatment is through a term he and his research team coined adaptive therapy.
"Adaptive therapy shifts the treatment paradigm of currently incurable cancers from the maximum tumor cell killing approach to what we might call the use of 'evolutionally enlightened' drug combinations that can stabilize the tumor," Gatenby said. "Our goal is to minimize the probability of the emergence of drug-resistant cancer cells, which are the ultimate cause of current cancer treatment failure and patient death."
The researchers will use breast cancer as their proof-of-concept tumor model, depending on laboratory tests and mouse models of breast cancer to carry out the studies, Gatenby said. They will enlist Positron Emission Tomography imaging to assess tumor chemotherapy resistance. This approach will ultimately inform clinicians about the presence and number of drug-resistant cells in a tumor.
"These approaches will be used to detect and measure tumor resistance and to suggest treatment strategies that prolong the duration of response to conventional breast cancer therapy," explained Gatenby.
Adaptive therapy is designed to promote competition between chemoresistant and chemosensitive cells, and to make the chemoresistant cells "less fit" than their chemosensitive counterparts, added Gatenby and colleagues.
As applied to cancer, natural selection, a key principle of modern biology, suggests that cancer consists of coalitions of distinct "microhabitats," some of which promote evolution of resistance to therapies. These same evolutionary principles of natural selection can be applied to successfully manage cancer, Gatenby said, and this concept is the foundation for adaptive therapy.
For Gatenby and his colleagues, cancer is subject to the evolutionary processes laid out by Charles Darwin in his concept of natural selection, the process by which nature selects certain physical attributes, or phenotypes, to pass on to offspring to better "fit" them to environmental pressures. The environmental pressure here is the cancer cell's microenvironment under attack from drugs aimed at killing cancer cells. Drug resistance routinely develops when cancer cells adapt to the chemotherapy.
"To improve adaptive therapy, we will examine mechanisms to exploit the cost of resistance to both detect resistant populations and also to suppress their proliferation," concluded Gatenby. "We will also study how the addition of estrogen during therapy intervals can be used to increase the fitness and maintain the number of hormonal therapy-sensitive cells."
|Contact: Kim Polacek|
H. Lee Moffitt Cancer Center & Research Institute