FEATURED INVESTIGATOR
DAVID J KWIATKOWSKI, MD, PHD

Dr. David Kwiatkowski is an acknowledged expert on tuberous sclerosis complex (TSC), a genetic disorder in which multiple tumors develop in different parts of the body of affected individuals. TSC occurs in about 1 in 6000 live births. Patients with this condition suffer from benign tumors in many different organs, including brain, kidney, lung, and skin. Although the tumors caused by TSC are histologically benign, several types can grow to a significant extent causing morbidity and/or death, and necessitating surgical or medical intervention. Clinically significant consequences of TSC include kidney failure, the progressive lung disease lymphangioleiomyomatosis (LAM), several types of brain tumors, seizures, and autism.

 

Dr. Kwiatkowski is also a practicing thoracic oncologist with expertise in all types of thoracic malignancy and a particular interest in therapeutic targeting and personalized medicine approaches to cancer patient care.

 

He is also a visiting scientist at the Broad Institute, and is involved in many cancer genome sequencing projects, including The Cancer Genome Atlas (TCGA) projects on bladder cancer, kidney chromophobe tumors, and mesothelioma.

Background

A graduate of the California Institute of Technology majoring in mathematics, Dr. Kwiatkowski received his Ph.D. from the Massachusetts Institute of Technology (MIT) in mathematics, and his M.D. from Columbia University’s College of Physicians and Surgeons. He did his postgraduate training at the Massachusetts General Hospital (MGH), and after his residency, fulfilled a postdoctoral fellowship in hematology-oncology, at which time he began to develop an interest in TSC while specializing in thoracic oncology. Recruited to the Brigham in 1991 by Tom Stossel, Chief of the Division of Hematology, Dr. Kwiatkowski has run the BWH DNA sequencing core facility for many years, and is an Assistant Director of the Partners Center for Personalized Genomic Medicine.

Research

Dr. Kwiatkowski’s greatest research achievement was the discovery of the TSC1 gene, one of the two genes that cause TSC when mutated, published in the journal Science in 1997. This discovery and work done in the fruit fly, Drosophila, led to the first hints about the function of the TSC1 and TSC2 protein products.  We now know that the TSC1/TSC2 protein complex has a critical role in regulating the activation of a master kinase called mTOR, which acts in a signaling pathway that controls cell growth. This critical pathogenic insight led to the discovery of a new use for an old drug, Rapamycin (sirolimus), which works to block mTOR (mammalian Target Of Rapamycin). A series of randomized and other clinical trials have led to approval of rapamycin or a related drug everolimus for the treatment of tumors that occur in patients with TSC. Dr. Kwiatkowski says, “This has been extremely gratifying to identify a gene, define its signaling pathway, and develop a therapy that is directed at the molecular basis of the disease and is effective.”  More recent studies both by Dr. Kwiatkowski’s lab and others have delineated the importance of mTOR signaling in a variety of cancers.  Furthermore, a variety of common cancers have mutations in either TSC1 or TSC2, and this appears to predict response to treatment with mTOR inhibitors.  More investigation is necessary however.

 

However, Dr. Kwiatkowski’s research interests do not end with TSC1, TSC2, and TSC.  He is very interested in personalized medicine and recognition of targetable mutations in cancer broadly.  His laboratory is currently working on projects in both bladder cancer and mesothelioma.

Laboratory

Dr. Kwiatkowski’s laboratory currently consists of a team of 3 post-doctoral researchers.  He has trained many students and fellows in the past from the high school level up to Assistant Professors.

funding

Dr. Kwiatkowski’s laboratory derives the bulk of its support from the National Institutes of Health National Cancer Institute and National Institute for Neurologic Disease and Stroke.

Collaborations

“Recruiting, developing, fostering, and mentoring associates” is a central feature of the laboratory, relates Dr. Kwiatkowski. “Nobody does this alone.” Having “high quality people come into your lab who are happy about the work they do, engaged, and focused is critical.” When asked whether the level of training and experience were also key factors, Dr. Kwiatkowski agreed that “postdoctoral fellows tend to be the most productive. They have already had significant research training and are able to take the project and move forward with it with less direction.” “But, you know,” he ventured, “I think interest and drive on the part of the person who comes to the lab is actually the most important thing. If they’ve got that, they’ll learn what it takes to get things done.”

Importance of Being at the Brigham

Dr. Kwiatkowski describes the atmosphere at Brigham and Women’s Hospital as highly conducive for making significant scientific breakthroughs. “For many years,” he states, “the Brigham has recognized, perhaps better than any other institution in the country and even the world, the importance of biomedical research.” In fact,” he adds, “support from one’s department chair, colleagues, and institution is probably the single most important aspect of developing one’s career and pursuing scientific discovery.”

 

In speaking about the nature of scientific discovery and importance of perseverance, Dr. Kwiatkowski shares his favorite story about renowned surgeon and cancer scientist, Dr. Judah Folkman, best known for his work on tumor angiogenesis. He recounts, “After delivering a lecture to medical students, Dr. Folkman was prompted for his personal view on the scientific process. Dr. Folkman replied, ‘It’s like night driving. You’ve got headlights on in front of you, you can see something out there, but there’s a lot of darkness all over the place, and you don’t know exactly where you’re going.’ ”

Selected References
  1. Guo Y, Du J, Kwiatkowski DJ. Molecular dissection of AKT activation in lung cancer cell lines. Mol Cancer Res. 2013 Mar;11(3):282-93.  PMID: 23319332
  2. Guo Y, Chekaluk Y, Zhang J, Du J, Wu CL, Kwiatkowski DJ. TSC1 involvement in bladder cancer: diverse effects and therapeutic implications. J Pathol. 2013  230:17-27. PMID:23401075
  3. Guo Y, Chirieac L, Bueno R, Pass H, Wu W, Malinowska I, Kwiatkowski DJ. Tsc1-Tp53 loss induces mesothelioma in mice, and evidence for this mechanism in human mesothelioma. Oncogene 2013 in press.
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