FEATURED INVESTIGATOR
CHARLES J DIMITROFF, PHD

A principal focus of Dr. Charles Dimitroff’s laboratory, established in 2003, is to understand how cancer cells metastasize, or spread, to distant sites and how tumors can evade the immune system. The central idea of Dr. Dimitroff’s work is that tumor cells use the same kinds of surface molecules that normal blood leukocytes (white cells) use to stick to blood vessels and creep into the tissues, where, in the case of cancer cells, they set up shop and grow into a metastatic tumor. In most forms of human cancer, it is the metastatic tumors that ultimately kill the patient, making metastasis one of the most important issues in cancer research.

 

Dr. Dimitroff’s scientific team is currently interested in understanding how melanomas utilize carbohydrates on their cell surface to evade the immune system and to facilitate their virulent behavior, such as the ability to invade, migrate and growth in local and distant tissues.

Background

A graduate of Columbia University, Dr. Dimitroff received his doctoral training at the Roswell Park Cancer Institute in upstate New York where he studied tumor biology and obtained a Ph.D. In 1999, he was recruited to Brigham and Women’s Hospital as a postdoctoral fellow by Dr. Robert Sackstein of the Department of Dermatology who was investigating why stem cells migrate or ‘home’ to bone marrow. As Dr. Dimitroff transitioned into an independent investigator within that department, he continued to work on problems related to tumor metastasis and cell migration to bone and to tumor-induced immune cell function.

Research

Dr. Dimitroff’s research focuses on understanding the glyco-molecular pathways regulating immune/tumor cell function and migration. As evidenced by his recent articles in J. Investigative Dermatology, J. Immunology, BLOOD, and Current Opinions in Immunology, the Dimitroff laboratory displays expertise in studies on galectins and their roles in inflammation and cancer. They have recently developed galectin-1 (Gal-1) fusion proteins (Gal-1hFc), which are analogous to native Gal-1, to analyze Gal-1 counter-receptor carbohydrate ligands on effector T cells, neutrophils and cancer cells. Though Gal-1hFc can elicit hallmark cell-death effects at high concentrations, they have shown for the first time that low physiologic levels of Gal-1 can profoundly influence T cell function. Gal-1 can encourage activated Th cells and even polarized Th1 and Th17 cells, T cell subsets classically involved in inflammation, to become IL-10-producing and regulatory in nature. This finding has revitalized the prospect of exploiting Gal-1 – Gal-1 ligand axis for controlling inflammation and cancer.

 

The Gal-1hFc construct is being developed as an anti-inflammatory therapeutic in autoimmune models of psoriasis, arthritis and multiple sclerosis. In related studies, the Dimitroff Lab has shown that analogs of glucosamine can block the synthesis of Gal-1 ligands on effector anti-melanoma T cells and thus avert Gal-1-mediated immunoregulation. Because melanomas produce an abundance of Gal-1, antagonizing Gal-1 effects on melanoma-killing T cells with glucosamine analogs represent a promising new and innovative method to boost anti-tumor immunity. This exciting pharmacologic approach is being piloted in the adoptive anti-tumor T cell cancer therapy setting. Additionally, they have made unanticipated observations that Gal-1 ligands are also conspicuously expressed (though not normal or benign melanocytes) and functionally correlated with malignant behavior on melanoma cells. The real excitement is the potential of detecting Gal-1 ligands as biomarkers melanoma malignancy.

Laboratory

The laboratory’s progress depends on a team of highly trained and dedicated scientific researchers. Dr. Dimitroff’s multi-faceted approach to biomedical research at HMS fosters a state-of-the-art, evolving laboratory that spawns successful scientists at every academic level and lends to a solid National/International reputation and continued NIH-funding. A dedicated teacher, Dr. Dimitroff fosters a didactic environment in the laboratory and is actively seeking new participants in this work of varying levels of experience including undergraduate interns, medical students, graduate students, and postdoctoral fellows. “I’m particularly looking for a student wishing to go to graduate school or medical school,” explains Dr. Dimitroff, “because they have the interest and drive to overcome some of the problems they may face in the lab and they have the intellectual ability to grasp some of the biological concepts that tend to be difficult, especially when I talk about carbohydrates and how they relate to the structure of adhesion molecules, a scenario that is not typically taught.”

funding

The bulk of Dr. Dimitroff ’s funding is from the Federal government through the National Institutes of Health.

Collaborations

Dr. Dimitroff and his colleagues enjoy numerous local, national, and international collaborations, and have relied heavily on the Dana Farber/Harvard Specialized Histopathology Services Laboratory, which is based in the pathology department at Brigham and Women’s Hospital.

Importance of Being at the Brigham

Working in the hospital environment where patients are treated surgically has been vital to Dr. Dimitroff’s work. Since the inception of his laboratory, Dr. Dimitroff has established more than a dozen collaborative projects both within and outside the Brigham and Women’s Hospital. “What makes conducting research at the Brigham transformative,” he explains, “is that there are numerous individuals who are physician–scientists. Because these researchers both care for patients and conduct wet lab research, there is always a translational component to their work that also influences the way I think about my own studies.  This emphasis, I believe, raises the overall impact of our data.”

Future

The translational aspect of Dr. Dimitroff’s work is the hope that, once fully-characterized in humans, galectin-1 and its binding partners can be targeted, therapeutically, to help alter the immune system to either: 1.) Dampen inflammation or 2.) Boost anti-tumor immune responses.

Selected References

1.  Cedeno-Laurent F, Opperman MJ, Barthel SR, Hays D, Schatton T, Zhan Q, He X, Matta KL, Supko JG, Frank MH, Murphy GF, Dimitroff CJ. Metabolic inhibition of galectin-1-binding carbohydrates accentuates anti-tumor immunity. J. Investigative Dermatology, 2012; 132(2):410-420.

2.  Cedeno-Laurent F, Opperman MJ, Barthel SR, Kuchroo VK, Dimitroff CJ. Galectin-1 triggers an immunoregulatory signature defined by IL-10 expression. J. Immunology, 2012; 188(7):3127-37.

3.  Cedeno-Laurent F, Watanabe R, Teague JE, Kupper TS, Clark RA, Dimitroff CJ. Galectin-1 inhibits the viability, proliferation and Th1 cytokine production of non-malignant T cells in patients with leukemic cutaneous T cell lymphoma. BLOOD, 2012; 119(15):3534-8.

4.  Dimitroff CJ. Leveraging fluorinated glucosamine action to boost anti-tumor immunity. Current Opinion in Immunology, 2013, 25(2):206-13.

X