Carlo C. Maley, Ph.D.

Assistant Professor
Molecular and Cellular Oncogenesis Program
Systems Biology Division
215-495-6838, Office

Introduction

The Maley laboratory is exploring fundamental concepts in neoplastic progression, the processes by which normal tissue becomes cancerous, for the purposes of developing better methods for cancer prevention and therapy. They are applying evolutionary biology, ecology, computational biology and genetics to the understanding of these problems.

Research Summary

The reason cancer is such a vicious disease, and so hard to cure, is that the cells in a neoplasm (an abnormal growth) evolve by natural selection. There are three necessary and sufficient conditions for natural selection, all of which are met in a neoplasm:

   1. There must be variation in the population. Neoplasms are mosaics of different mutant cells.
   2. That variation must be heritable. The variation in a neoplasm is due to mutations and methylation of the DNA in the cells. The variation is thus passed down to both daughter cells when a neoplastic cell divides.
   3. The variation must affect reproduction or survival. Most of the hallmarks of cancer are examples of mutations that give a reproductive or survival advantage to the mutant cell. This includes uncontrolled proliferation, suppression of apoptosis (programmed cell death), stimulation of new growth of blood vessels to feed the neoplasm, evasion of the immune system, and invasion of other organs.

A consequence of this evolution within a neoplasm is that a treatment will tend to kill the susceptible cells but leave the resistant ones to flourish. A few months later, the cancer will reappear and will be resistant to the previous treatment. Thus, evolution lies at the heart of both neoplastic progression and our difficulties in treating cancer.

The Maley laboratory is applying evolutionary and ecological theory to neoplastic progression and cancer therapy in order to modulate the evolution of neoplastic cells and thereby prevent cancer and its relapse. They take three, mutually reinforcing approaches to these problems: computational simulations to explore hypotheses, data mining  of (application of evolutionary theory to) genetic data from neoplasms, and evolutionary experiments in tissue culture.

Current projects in the lab include:

• Measuring genetic diversity in neoplasms and testing if it predicts both progression and therapeutic resistance.
• Applying phylogenetic methods to measure the parameters of evolution in neoplasms.
• Developing in vitro competition assays to find cancer prevention drugs.
• Developing experimental models of Barrett’s Esophagus.
• Harnessing clonal evolution to prevent cancer.
• Computational modeling of the mechanisms of clonal expansion.
• Computational modeling of neoplastic progression.

Recent Scientific Advances

Clonal Evolution and the Prediction of Progression to Cancer: In order to study the evolution of clones within a neoplasm, the Maley laboratory has focused on patients with Barrett's esophagus, a pre-malignant neoplasm associated with chronic gastric reflux (heartburn). Only about 5-10% of people with Barrett's esophagus will progress to esophageal adenocarcinoma, so surveillance with periodic endoscopic biopsies is recommended to detect a cancer early when it is still easily curable. In the meantime, the genetics and population sizes of mutant clones in the biopsies can be analyzed in order to illuminate the evolutionary processes that lead to cancer.

In collaboration with the Seattle Barrett's Esophagus Research Program at the Fred Hutchinson Cancer Research Center, Maley and colleagues have shown that abnormalities in the tumor suppressor genes p16 and p53 are selectively advantageous and are associated with clonal expansions.  Other mutations detected in chromosomes 9 and 17 appear to be evolutionarily neutral hitchhikers on those expansions.

A current debate in cancer research centers over the relative importance of genetic instability, or high mutation rates, and clonal expansion. Evolutionary theory predicts that the rate of evolution in a population is proportional to both the size of the population and its mutation rate. When the investigators estimated the surface area covered by mutant clones in Barrett's esophagus, a measurement of cell population sizes, patients with larger mutant clones were found more likely to progress to cancer than patients with smaller clones. This was true for aneuploid clones, that is clones with the wrong number of chromosomes, and for clones carrying a p53 abnormality.  Both aneuploidy and p53 loss are associated with genetic instability. However, the size of clones with p16 abnormalities did not predict progression to cancer. Thus, it is the combination of clonal expansion and genetic instability that predicts neoplastic progression.

Development of Novel Cancer Prevention Methods: The Maley laboratory is developing computational models of clonal evolution in neoplasms as test beds for the development of novel strategies to prevent and possibly cure cancer. By simulating the evolution of resistance, they are able to test ideas in silico for preventing resistance and relapse. Two strategies have shown particular promise in these models: Benign Cell Boosters and the Sucker's Gambit. A Benign Cell Booster is a drug that, instead of killing the neoplastic cells, increases the fitness of the relatively benign cells. This allows the benign cells to out-compete the relatively aggressive cells in the neoplasm and drive the aggressive cells to extinction. If such a drug can be found it should not select for resistance and it should be relatively non-toxic, since it does not kill cells directly. While a Benign Cell Booster may increase the size of a tumor, it would result in a benign tumor that could be removed surgically. This strategy is only successful if the Benign Cell Boosters selectively benefit only the benign cells and so they must act through a mechanism that is intrinsic to the benign state. It is unclear if such a drug exists. The Maley laboratory is now investigating likely candidate agents.

The Sucker's Gambit is a strategy to enhance the efficacy of traditional cancer chemotherapies. The models suggest that if a drug could be used in a preparatory regime to select for chemosensitive clones in the neoplasm, then resistant clones may be driven to extinction and the  subsequent use of a chemotherapy would be more likely to completely cure the cancer. This might be achieved by using a nutrient or mitogen that mimics the chemotherapy drug. The Maley laboratory is now testing this idea in cell cultures.

Selected Publications

Pepper, J., Sprouffske, K., Maley, C.C.: Cell Differentiation Patterns Suppress Somatic Evolution. PLoS Computational Biology, 3:e250, 2007.

Maley, C.C., Galipeau, P.C., Finley, J.C., Wongsurawat, V.J., Li, X., Sanchez, C.A., Paulson, T.G., Blount, P.L., Risques, R., Rabinovitch, P.S. and Reid, B.J.: Genetic clonal diversity predicts progression to esophageal adenocarcinoma. Nature Genetics, 38:468­473, 2006.

Maley C.C. and Reid B.J.: Natural selection in neoplastic progression of Barrett's esophagus. Semin. Cancer Biol. 15:474-83, 2005.

Maley, C.C., Galipeau, P.C., Li, X., Sanchez, C.A., Paulson, T.G., Blount, P.L., Reid, B.J.: The combination of genetic instability and clonal expansion predicts progression to esophageal adenocarcinoma. Cancer Res 64:7629-7633, 2004.

Maley, C. C., P. C. Galipeau, X. Li, C. A. Sanchez, T. G. Paulson, P. L. Blount and B. J. Reid. 2004. Selectively advantageous mutations and hitchhikers in neoplasms: p16 lesions are selected in Barrett s Esophagus. Cancer Research. 64:3414 3427.

Maley, C. C., B. J. Reid, and S. Forrest. 2004. Cancer prevention strategies that address the evolution of neoplastic cells: Simulating benign cell boosters and selection for chemosensitivity. Cancer Epidemiology, Biomarkers and Prevention. 13:1375-84.

Maley, C. C. and B. J. Reid.  2003.  Barrett's esophagus as an example of the evolution of cell lineages in cancer.  Encyclopedia of the Human Genome.  London, UK: Nature Publishing Group.