HARVARD COLLEGE, PRESIDENT & FELLOWS OF

Relapse after therapy remains a critical problem for most types of cancer in humans, even when cancer-specific therapy is initially effective. Understanding the basis for cancer resistance and recurrence is a critical pre-requisite for developing more effective treatments. Recent data indicate that in some cancers, including leukemia, colon cancer, and certain brain tumors, a minority of cells in the initial tumor possesses unique properties reminiscent of normal tissue stem cells: a capacity for extensive self-renewal and differentiation potential. Relative drug resistance in these cells may be especially relevant for cancer recurrence. Thus, it is important to understand the precise relationship between these tumor-initiating cells and stem cells found in normal tissue, as key differences might be exploited for therapeutic benefit. In this project we outline an approach to identify critical similarities and differences in the genetic material of normal and cancer stem cells isolated from normal intestine/colorectal cancer, neural stem cells/glioblastoma multiforme (GBM) and hematopoietic stem cells/acute myelogenous leukemia (AML). We will isolate cancer stem-cells from human tumors and mouse models of cancer, and we will compare them with normal tissue stem cells. The analysis will provide an unprecedented and comprehensive picture of normal and cancer stem cells, highlighting key differences that may be exploited therapeutically. The dataset and concomitant analysis will be made available as a resource to the stem cell and cancer research communities. To complement these efforts, we will also develop sophisticated mouse models of four signaling pathways that play seminal roles in cancer stem cell biology. In sum, the studies proposed in this highly collaborative project will provide vital information to aid in developing therapies that might target cancer stem cells while sparing their normal counterparts.

Clarification of Codes