Founded in 1884, the New York City institute known today as Memorial Sloan-Kettering Cancer Center (MSKCC) is the world's oldest and largest private cancer center.
Founded in 1884, the New York City institute known today as Memorial Sloan-Kettering Cancer Center (MSKCC) is the world’s oldest and largest private cancer center. The facility started out as the New York Cancer Hospital. A new edifice was built in 1939, and the institution was rechristened Memorial Hospital. In the 1940s, former General Motors executives Alfred Sloan and Charles Kettering established the Sloan-Kettering Institute, which was built adjacent to Memorial Hospital, to conduct scientific medical research. The two entities consolidated in 1960, and today, MSKCC is widely recognized as one of the world’s premier biomedical research institutions and cancer care facilities. MSKCC has more than 10,000 employees, including 727 attending staff. In 2008, more than 22,000 patients were admitted to the hospital, and MSKCC’s Manhattan and regional sites cumulatively logged more than 466,000 outpatient visits.
Research has long been recognized as an essential component of patient care at MSKCC, and when it comes to cancer, the center has remained at the forefront in terms of new approaches and scientific breakthroughs. In 2006, the center opened a 23-floor research building to expand on many of its projects and take on new ones. Next door to the research building, construction is currently under way on a 7-floor laboratory. MSKCC’s enduring dedication to educating and training generations of researchers and physicians has seen the institution rewarded with a reputation among patients and the scientific community as one of the nation’s leaders on a wide range of cancers.
Linking Parkinson’s Disease and Cancer
One project MSKCC has been working on is determining possible links between Parkinson’s disease and malignancy. In 2009, Timothy Chan, MD, a radiation oncologist and member of the Human Oncology and Pathogenesis Program and the Brain Tumor Center at MSKCC, led a multidisciplinary team of the institution’s investigators to what he termed a “surprising discovery.” They found that the PARK2 gene, responsible for an inherited form of Parkinson’s disease, plays a role in several types of cancer, including colon and lung cancers and glioblastoma.
“You couldn’t really have two diseases that are more different,” explained Chan. “Parkinson’s is a neurodegenerative disease. When the neurons in the mid-brain die, the result is motor function is disrupted. In cancer, it’s just the opposite…you have uncontrolled growth, with cells spreading everywhere.”
The PARK2 gene encodes a protein known as parkin, which regulates cell division and proliferation. Chan’s team found that somatic mutations in the PARK2 gene on chromosome 6q25.2-q27 interfere with parkin’s ability to ubiquitinate and degrade cyclin E. Accumulation of cyclin E accelerates the cell cycle and cell division becomes rampant, increasing the likelihood of cancer. Chan suspects a similar process is at work in Parkinson’s, which is associated with germline mutations in this same area of the chromosome. The cyclin E builds up in the neurons, inciting them to attempt to divide. The problem is that the neurons cannot divide and consequently die. The area on chromosome 6 where these PARK2 mutations are found is known to play a contributing role in many types of cancer.
Chan said his team’s discovery provides a conceptual framework for combating and treating different forms of cancer. “This defines a pathway in which cancers grow more and more aggressively and out of control,” he explained. “It helps explain all the tumors with chromosome 6 loss, which is a large number. From a pure numbers perspective, this finding identifies the gene and hence the pathway responsible.” Chan said now that they have determined the pathway involved, researchers can examine it for targets that might prove useful in inhibiting the undesirable oncogenic behavior.
Chan believes the MSKCC group’s discovery will open doors not only in cancer research, but also in Parkinson’s. “I think the neurologists and people studying Parkinson’s disease as a neurologic disorder will have a clue now to look for events that cause the disease in the general population.”
Moving forward, Chan said new research will focus on developing animal models to test therapeutics in development that might target the disruptive pathway. “We’re now able to make some sense in an intellectual framework that explains the primary defect in a lot of different cancers,” he added.
Using Molecular Diagnostics
Researchers at MSKCC believe that the key to treating men and women with lung cancer lies in gaining a better understanding of the genetic makeup of each person’s tumor. By using molecular diagnostic testing to pinpoint specific mutations associated with more than one-third of lung cancer cases, oncologists maximize the chances of treatment success.
Marc Ladanyi, MD, is chief of MSKCC’s Molecular Diagnostics Service and director of the Diagnostic Molecular Pathology Laboratory. He has been much more than an eyewitness to the growth of molecular diagnostics over the last two decades.
“This is a field that has been in existence since the early 1990s, but it was originally focused on leukemia and lymphoma diagnosis,” Ladanyi said. “That was the starting point, at least in cancer. But in recent years it has really exploded with the identification of mutations in common solid tumors.”
Ladanyi said when researchers discovered mutations in lung cancer in 2004, several cancer centers quickly realized that molecular testing was going to be a new paradigm for treating the disease. Since then, Ladanyi and his colleagues have seen the field rapidly transform.
Recently they decided to expand the spectrum of genetic mutation testing for MSKCC patients beyond EGFR and KRAS in lung cancer and KRAS and BRAF in colorectal cancer. They are now conducting up-front testing of lung and colorectal tumors for other mutations with the potential to guide treatment selection in the near future, most likely in the context of clinical trials.
“The philosophy here is that we analyze the patient’s tumor and have that information available for when the patient progresses,” Ladanyi said, and he described it as a “new way of thinking” about personalized care. “Instead of waiting for the patient to progress and then trying to get material to look for mutations for targeted therapies that are in clinical trials, we have the information ahead of time.”
That information is then made available to the oncologist. “It’s just another aspect of characterizing a patient’s tumor,” Ladanyi explained. This proactive approach enables oncologists to prequalify patients for clinical trials. If a patient fails to respond to an approved therapy, the patient’s clinician will already know whether the patient has any mutation appropriate for a targeted agent being investigated in an open clinical trial.
That approach is embodied in the Lung Cancer Mutation Analysis Project (LC-MAP), which MSKCC launched in January 2009. In this program, pathologists look for all known mutations in tumor samples from patients diagnosed with lung adenocarcinoma. Once the LC-MAP molecular analysis is completed, individuals with an EGFR mutation whose cancer has spread from the lung are offered treatment with erlotinib (Cetuximab), an EGFR inhibitor. MSKCC is also investigating erlotinib in the neoadjuvant and adjuvant settings for lung cancer patients with EGFR mutations. The molecular analysis will allow clinicians to identify those patients without an EGFR mutation and treat them with a drug other than erlotinib, which would be unlikely to benefit them.
“This is a model that we’re now implementing clinically,” Ladanyi said. He added that the New York State Department of Health had recently given MSKCC approval to offer Sequenom testing for EGFR, KRAS, and BRAF. “We’ll move our routine clinical testing to the Sequenom platform,” he said, “which will allow us to generate a wider mutational profile of those genes.”
New Pituitary Tumor Center
Three years ago, MSKCC established the Pituitary Tumor Center. Not long after, the number of pituitary cases treated at MSKCC rose from 3 to 4 each year to approximately 200. Benign tumors of the pituitary gland are extremely common, said Viviane Tabar, MD, a researcher and neurosurgeon at MSKCC. While a large number of pituitary tumors are never diagnosed, they have the potential to cause a wide range of problems for patients, ranging from gigantism, changes in the voice, sleep apnea, and—for younger women—problems with menstruation or fertility.
Tabar recognized that MSKCC had a unique capability to treat these benign tumors and was a driving force behind the opening of the Pituitary Tumor Center. “I was very sensitive to the fact that patients with pituitary tumors usually need to see a neurosurgeon, an endocrinologist, and an ophthalmologist in order to get a comprehensive assessment of the tumor and its impact,” Tabar said. She pointed out how challenging it can be for patients to coordinate this process. “Patients have to arrange for these appointments, make sure the doctors are communicating, and [ensure] that the tests done in three different places are communicated. I wanted to integrate all of that in one clinic,” explained Tabar.
The neurosurgeon’s fascination with the pituitary gland and empathy for patients with pituitary tumors is evident. Tabar said the gland produces “lots of fascinating hormones,” and when a tumor results in overproduction of one of these hormones, it can result in dramatic changes to a person’s life.
“If [the tumor] is making a growth hormone, there are devastating changes—anything from becoming a giant to having distorted facial features, joint pain, and heart disease—all of them caused by excess of one tumor,” Tabar said. In some cases, particularly for adults, Tabar said the manifestations of a pituitary tumor might be subtle but can result in huge expense and frustration. Patients might spend thousands of dollars on dental work to realign their teeth, never realizing that excess growth hormone from an underlying pituitary tumor was causing the problem. “[In this case,] the symptoms were diagnosed and treated, but not the etiology,” said Tabar, who stressed that with proper diagnosis and treatment, pituitary tumors are survivable.
For cases in which surgery is required, the use of intraoperative MRI allows Tabar and her colleagues to create new images of the pituitary gland continually during the procedure. Tabar said the benefits are significant. “I can tell immediately if I have resected the entire tumor, [or] if there’s residual and if it’s safe to go after it. Getting the sort of live imaging instead of relying on a scan from yesterday is a huge advantage.” It is also a major benefit to patients passing through the doors of the world’s oldest and largest private cancer center.
Patients in Brooklyn, New York, will soon find it easier to pass through the doors of MSKCC. In April, the hospital announced that it would be opening an outpatient center in the city “sometime after Labor Day.” The purpose of the 7745-sq ft center is to provide chemotherapy services to as many as 30 MSKCC patients each day, and it will not include a laboratory or pharmacy. It is just one more way that MSKCC works to make patients’ lives easier and better.