Jacob Scott, M.D., Ph.D., a physician researcher from Cleveland Clinic’s Department of Translational Hematology and Oncology Research, recently received a $2.8 million grant from the National Cancer Institute, part of the National Institutes of Health, to study how ecological and evolutionary mechanisms contribute to lung cancer development and progression, and how the interplay between these mechanisms may provide novel treatment insights.
With this new grant, Dr. Scott will build on two major research efforts he published earlier this year. The first of which, published in Nature Ecology and Evolution, detailed the first-in-class test he and his team developed to directly quantify and describe the ecological forces (interactions within the cell) and evolutionary mechanisms (cell mutation and selection) that lead to the treatment resistance commonly observed in cancer cells. In this work, the researchers measured and compared growth rates of non-small cell lung cancer cells sensitive and resistant to the drug alectinib. The study offered important insights into when and under what conditions resistant cells win over sensitive cells.
The new funds will enable Dr. Scott’s laboratory to continue this line of investigation—this time not just measuring conditions when resistant cells overpower sensitive cells, but to also manipulate the cells.
“Due to the heterogeneous nature of most tumors, developing a single silver bullet is not necessarily the answer to treating cancer,” said Dr. Scott who is also a practicing oncologist in the Department of Radiation Oncology, Cleveland Clinic Taussig Cancer Institute. “We may already have effective treatments within reach and need to identify the optimal combination and sequence to tackle each individual cancer.”
Dr. Scott’s second effort will dig deeper into advances described in a paper published in Nature Communications. In that publication, he and his team defined a quantitative measure of the probability of collateral sensitivity—a phenomenon observed when treatment with one drug leads to susceptibility to a second— which laid the groundwork for finding genomic indicators of this drug resistance.
Leveraging this effort, the research team will search for patterns in drug sensitivity and resistance in an effort to better understand when the switch from sensitivity to resistance flips, and what molecular characteristics may be predictive of that change. Defining these molecular hallmarks will be a critical step in identifying clinically meaningful information that may help clinicians better track the progression of a patient’s cancer and anticipate necessary changes in treatment plans. Understanding the role that time plays in these transitions will be equally important.
“The question we are most interested in answering is not ‘which treatment is best?’ but ‘in what combination and order is best?’” said Dr. Scott. “Understanding the ecological and evolutionary dynamics, how to interrupt them, and how to tell when the balance starts to tip towards resistance will be crucial in getting to the bottom of that question.”