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On Target - Cancer Damage Control

Winter 2009

Cancer Damage Control

Date: December 1, 2009

After an extensive, two-year search for a world-class research  scientist and program leader, in August, 2007, Theodore L. DeWeese, M.D., department chairman of the Department of Radiation Oncology and Molecular Radiation Sciences at Johns Hopkins, hired Marikki K. Laiho, M.D., Ph.D., as the new director of the Division of Molecular Radiation Sciences. Dr. Laiho was the director of the Molecular Cancer Biology Program at the University of Helsinki.

With a background in cancer biology, Dr. Laiho brings her expertise in DNA-damage signaling to her laboratories at Johns Hopkins and in Helsinki. At Johns Hopkins, Dr. Laiho leads a research division that focuses on the basic, mechanistic aspects of cellular responses to genetic lesions. When many lesions go undetected, five to ten critical sites in a cell’s DNA may unhinge the normal cell.

She seeks to understand the mechanisms involved in the conversion of normal cells to cancer cells. The question of how cancers originate is extremely relevant to the practice of radiation oncology and the field of radiobiology, the science of how damage lesions are generated and how repaired.

Dr. Laiho manages her laboratory by allowing team members, including students, to take relatively independent charge of their projects. The scientists formulate different research questions and focus their work accordingly, while being cognizant of the overall objective of the laboratory and their contribution to it.

The researchers frequently meet with Dr. Laiho to discuss progress. Dr. Laiho trusts those under her supervision to use their technical skills to make rational decisions, but, she stresses her role in the training purpose of the laboratory.

Dr. Laiho knows she is helping to create the next generation of topnotch scientists. She recently recruited assistant professors Sonia Franco,M.D., Ph.D., and Mihoko Kai, Ph.D., to work specifically on various aspects of DNA-damage response; how cells sense and repair this damage.

The sensing, detecting, and repairing of DNA lesions are of vital importance
in maintaining genomic integrity. In advanced cancer, many pathways that govern proper DNA-damage control are lost. Conditions prevail which augment the accrual of genetic errors, which leads to the proliferation of cancerous cells.

When tumors are targeted by radiation, powerful signals are leashed in the cell, which together with the physical damage, lead to the death of the cancer cell. Because of the many genetic lesions already present in the cancer cell, and the inability of tumor cells to repair effectively the excess of the damage, the damage overload proves critical. Several
modes of cancer therapies, including many cytotoxic drugs, exploit this vulnerability of tumor cells.

Dr. Laiho is particularly interested in the function and regulation of the key DNA-damage response protein, the p53 tumor suppressor. The p53 protein is one of the crucial chains being mutated in most human cancers.

Although medical scientists around the world are investigating p53, Dr. Laiho focuses specifically on the mechanisms mediating the activation of p53 in response to cell stress, and, on attempts to revoke its activity. The activation of this protein may be involved in the sensitivity of cancer to radiation.

Dr. Laiho examines how normal tissues respond to radiation. She has observed altered p53 and DNA-damage checkpoint responses in the prostate gland and posits that “our observations…indicate that the relaxed damage control could predispose the prostate to the highly frequent tumorigenic processes observed clinically.” Dr. Laiho’s goals are: to
acquire groundbreaking information on the regulation of cellular DNA damage and tumorigenesis pathways; to provide novel, lead compounds that activate p53 for preclinical trials;and to identify novel targets for therapy. Dr. Laiho aims to narrow, if
not close, the gap between research and its clinical application, between present knowledge and research goals and the future aims of science, medicine, and the work of Johns Hopkins.

Dr. Laiho’s work is part of the multidisciplinary continuum at Johns Hopkins, as basic research flows from the laboratory to the clinic to benefit all patients who come here seeking treatment for cancer.

Articles in this Issue

Letter From The Chairman

Cancer Treatment Heats Up

Cancer Damage Control

The Scale of Cancer Treatment

Zooming in on Breast Cancer


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