Exploiting Darwin to Overcome Drug Resistance in Leukemia

Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy. Although most children with ALL are cured, many still die from their disease; consequently, many investigators are developing new therapies targeting leukemias with mutations involving CRLF2, IKZF, JAK, or ABL, as they represent subsets of patients with particularly poor outcome. Recently, significant clonal diversity was found in ALL and other cancers, even at diagnosis. This observation may have significant implications for the success of targeted therapies that may eradicate one clone but allow others to survive and propagate, because it implies that eliminating the dominant clone may not be sufficient to cure the child.

We hypothesize leukemic cells undergo a series of changes driven by Darwinian natural selection that result in clonal diversity and differential responses to chemotherapy. To test this model, we propose to grow in immunodeficient mice, leukemia cells from patients with CRLF2-driven leukemia who either were or were not cured of their disease to assess the spectrum of clones and mutations associated with response or resistance to therapy. We will treat these cells with steroids or anthracyclines, two mainstays of ALL therapy, to determine by whole-exome sequencing whether treatment differentially modifies this spectrum. By modeling the evolution of clonal diversity, we hope to identify mutations conferring a selective advantage to clones in the face of treatment. This knowledge can be used to identify targets and effective therapies for resistant clones and may serve as a proof of principle by which evolutionary methods can be harnessed to reveal critical biological insights into leukemia. We expect that the synergy between evolutionary biologists and leukemia biologists induced by this proposal will not only identify new paradigms in cancer biology and therapy, but will form the foundation for a new evolutionary medicine discipline at a unique institutional nexus of extraordinary strength.

Dr. Kenan Onel is an expert in pediatric and other familial genetic cancer syndromes. The goal of Dr. Onel’s research is to understand the genetic basis of cancer susceptibility by identifying genes and genetic markers that alter cancer risk. These markers may be directly translatable into simple blood tests by which the genetic contribution to cancer risk can be determined. This research may also lead to the discovery of targets for new molecularly engineered cancer treatments.
In the clinic, Dr. Onel cares for people who may be at an increased risk for cancer, and families in which cancer is common. The focus is on assessing individual and familial cancer risk, and then developing individualized cancer prevention strategies for those found to be at increased risk.