Laboratory Research
On this page
- Epidemiology of Lung Cancer
- Chemoprevention of Lung Cancer
- Molecular Targets for Small Cell Lung Cancer
- Molecular Targets for Non-Small Cell Lung Cancer
- Cell Cycle Control in Non-Small Cell Lung Cancer
- Brain Metastases in Lung Cancer
- Lung Cancer in Young Patients
- Restoring normal growth in lung cancer cells
The Lowe Center for Thoracic Oncology Program is dedicated to finding new and better ways to treat patients with thoracic cancers. In addition to directing research programs at Dana-Farber Cancer Institute, Brigham and Women's Hospital, and Harvard Medical School, our physicians are leaders in national cooperative group studies through the Cancer and Leukemia Group B.
Such efforts have led to a full-scale attack on thoracic cancers. New drug combinations and multimodality therapies are significantly improving survival rates for patients with non-small-cell lung carcinomas. For small-cell carcinomas, which rapidly develop drug resistance and typically recur within two years, increased cure rates have been achieved with high-dose chemotherapy and the reinfusion of autologous bone marrow cells or peripheral blood progenitor cells to rapidly restore blood counts.
The program also is advancing minimally invasive methods to diagnose and treat lung cancer, such as video-assisted thoracic surgery. For malignant mesothelioma, research has shown the lives of some patients can be extended by aggressive surgery followed by chemotherapy and radiation therapy.
The biology of thoracic cancers is a promising area of research. To expedite the study of molecular and cellular mechanisms that lead to cancer, the Thoracic Oncology Program has established a bank of frozen tissue specimens. Strategies designed in the laboratory to kill cancer cells selectively or to halt their spread are now being adapted to the clinical setting.
Below is a summary of other key research efforts at the Lowe Center.
Epidemiology of Lung Cancer
David Kwiatkowski, MD, PhD, Principal Investigator
Cigarette smoking causes the majority of lung cancers in the United
States. However, the same exposure to cigarettes can cause lung cancer
in some smokers while sparing others. In addition, about 10 percent of
lung cancers in men and 20 percent in women occur in patients who do
not smoke. There is an ongoing effort in the Harvard Medical School to
determine the exposures of our patients who develop lung cancer. The
General Thoracic Surgeons have been banking away from the patients
with lung cancer for nearly 10 years. There are efforts to determine
the genetic changes in the lung cancers and relate them to the
exposures of the patients. This will be an important step to determine
potential environmental causes of lung cancer and provide information
about eliminating carcinogenic material from the environment.
Chemoprevention of Lung Cancer
Pasi Jänne, MD, PhD, Principal Investigator
Lung cancer is the most common cause of cancer deaths in the United
States. Approximately 85 percent of patients developing lung cancer
will go on to die of their cancer with currently available
treatment. The major public health approach to this is reducing
cigarette smoking in the United States. This involves preventing young
people from starting to smoke cigarettes and getting those who are
currently smoking to stop. The policy has been partially successful
because lung cancer deaths in the United States have started to
fall. Despite this, more than 100 million current and ex-smokers are
at risk for developing lung cancer.
An animal model has been developed where mice develop about 100 lung cancers 4-8 weeks after they are born. We have tested agents, which may prevent the development of these lung cancers. If successful, we will apply these to patients who have undergone resection of a lung cancer to prevent the development of a new lung cancer.
Molecular Targets for Small Cell Lung Cancer
Ravi Salgia, MD, PhD, Principal Investigator
Small cell lung cancer (SCLC) is an aggressive cancer and leads to
very early metastasis. We have been studying the role of various
receptors in the etiology of small cell lung cancer. We have shown
that receptor tyrosine kinases are an important pathway in these
tumors, and have started to target them in clinical trials. As an
example, the receptor tyrosine kinase c-Kit is expressed 70 percent of
the time in small cell, and there is a specific inhibitor STI571 that
target this receptor in cell lines. Based on this, there is a clinical
trial of STI571 in patients with small cell lung cancer. Now, we are
in the process of taking the patient specimens and analyzing various
molecular/cellular parameters to correlate with potential response to
therapy.
Also, since SCLC tends to metastasize early and often, we have begun to study the role cell motility plays in metastasis to the lymph nodes and bone marrow. We have a unique system to study the cell motility called time-lapse video microscopy (TLVM). Utilizing TLVM, we can determine the rate of migration, the various protein components involved in cell motility of SCLC, and the response to inhibition of motility by novel therapeutics. Eventually, we would like to prevent metastasis of SCLC; these studies may provide us with novel targets.
Molecular Targets for Non-Small Cell Lung Cancer
Bruce Johnson, MD, Principal Investigator
Over the past few years, significant advances have been made in the
understanding of lung cancer biology. Many of these findings are now
being translated clinically, and are forming the basis for the
development of new drugs for advanced disease, providing new hope for
patients. For example, we now have a sophisticated understanding of
the genetic changes that occur that cause normal lung cells to become
cancerous. Some genes, known as oncogenes, are abnormally activated in
tumor cells. Other genes, which normally prevent cells from becoming
cancerous (tumor suppressor genes), are missing in tumor
cells. Several new drugs aimed at inhibiting oncogenes or replacing
tumor suppressor genes have entered clinical trial at the Lowe
Center. For example, we are participating in clinical trials using
drugs directed at the ras oncogene (farnesyl transferase inhibitors),
the epidermal growth factor receptor tyrosine kinase (Iressa) and
protein kinase C (ISIS 3521). Several of these have shown significant
promise when used alone or in combination with standard chemotherapy
agents.
Cell Cycle Control in Non-Small Cell Lung Cancer
Geoffrey Shapiro, MD, PhD, Principal Investigator
Cyclin-dependent kinases (cdks) are a critical set of enzymes that
govern the growth and division of cells. In normal cells, these
enzymes are held in check by inhibitors that exert tight control over
their activity. These inhibitors are missing in tumor cells. A new
class of drugs, known as cdk inhibitors, is currently under
development. Inhibiting cdks in lung tumor cells has been shown to
stop their growth and to cause tumor cell death.
Flavopiridol is the first cdk inhibitor to reach clinical trial and is undergoing testing in lung cancer patients at the Lowe Center. Several patients have achieved impressive disease stability. In addition, preliminary results indicate that Flavopiridol can enhance the effects of standard chemotherapy agents used against lung cancer. The mechanisms by which cdk inhibitors interact with chemotherapy are currently a major focus of research. Clinical trials combining Flavopiridol with standard chemotherapy drugs are underway.
Brain Metastases in Lung Cancer
Lung cancer is the most common type of cancer to spread to the brain. The development of cancer spread to the brain during the treatment of lung cancer can include symptoms of headache, nausea, vomiting, balance and gait problems, muscle weakness, and memory problems. The chemotherapy given to patients with lung cancer does not get into the brain very well, so in many patients, the chemotherapy can be causing the cancer to shrink in the lung and other parts of the body, but grow in the brain.
The treatment for cancer spread to the brain can include irradiation to the whole brain, irradiation localized to the cancer spread to the brain and even surgical removal of the cancer. These treatments, in combination with other treatments, can cure some patients with lung cancer that has spread to the brain. The research that can be started here at the Lowe Center for Oncology is to set up a system to follow our patients to find out how many get cancer spread to the brain, the most effective means of treatment, and the outcomes of this treatment.
Lung Cancer in Young Patients
David Kwiatkowski, MD, PhD, Principal Investigator
Lung cancer occurs most often in older patients, but occurs about 10
percent of the time in patients younger than 50 years old, and about 2
percent of the time in patients younger than 40 year old. Although
rare in the general population of lung cancer patients, many of these
patients from throughout New England are seen at the DFCI Thoracic
Oncology Program. The fact that cancer occurs in these young patients
while only 20 percent of lifetime smokers develop lung cancer suggest
that there are genetic factors which cause the development of lung
cancer in these young patients. In this study, we propose to collect
detailed clinical information on a large number of young patients with
lung cancer, and to study the genetic factors that may account for
their acquisition of lung cancer.
Restoring normal growth in lung cancer cells
Barrett Rollins, Principal Investigator
Lung cancers occur when something disrupts the genes that regulate the
normal growth of lung cells. This can happen by wholesale deletion of
the gene, by mutations that inactivate the gene, or by gene
"silencing." This last process occurs frequently in lung
cancers and is caused by an enzyme that transfers chemical methyl
groups specifically to the DNA of those genes. We have found that two
of these enzymes, called DNA methyltransferases, are directly involved
in the malignant transformation of normal lung cells; we are
developing drugs and gene therapy agents that will reverse this
process.
