Memorial Sloan-Kettering's Brain Tumor Center Cultivates Collaborations

The co-leaders of Memorial Sloan-Kettering's Brain Tumor Center -- (from left) neurosurgeon and cancer biologist Eric Holland, Chair of the Department of Neurology Lisa DeAngelis, and Chair of the Department of Neurosurgery Philip Gutin.

Brain tumors -- both primary tumors and brain metastases -- are among the most difficult cancers to manage. Despite advances in understanding and treatment that have improved patient outcomes, challenges remain. To address them, Memorial Sloan-Kettering has established a Brain Tumor Center (BTC) under the direction of Eric C. Holland, neurosurgeon and cancer biologist and incumbent of the newly established Emily Tow Jackson Chair in Oncology; Lisa M. DeAngelis, Chair of the Department of Neurology; and Philip H. Gutin, Chair of the Department of Neurosurgery.

"The BTC was conceived as a center without walls -- a multidisciplinary effort that would encompass research from the laboratory to the clinic -- which, by extension, includes clinical care," said Dr. DeAngelis.

"Putting Memorial Sloan-Kettering's basic science people together with neurosurgeons and medical oncologists and radiation oncologists -- everyone who treats brain tumors -- facilitates the exchange of ideas among investigators with conjoined interests," elaborated Dr. Holland. "We're taking what is already a diverse group of people and projects at Memorial Sloan-Kettering and making the BTC a forum for new and enhanced collaborations."

The BTC holds weekly meetings where scientists and clinicians from both within Memorial Sloan-Kettering and outside the institution are invited to present their research. "Everyone in the room is interested in one way or another in brain tumors," Dr. DeAngelis noted, "and as people hear what their colleagues are doing, productive interactions begin." The BTC is planning annual retreats, with the first one to take place in 2008.

Research undertaken through the BTC is grounded in work to elucidate the cascade of genetic events that promote tumor development and growth and, in turn, to translate that understanding into strategies for treatment. The development of new therapies is dependent in large part on performing preclinical studies in animal models, and Dr. Holland's laboratory has created realistic mouse models of several gliomas, including glioblastoma, the most lethal form of brain tumor in humans. These models allow researchers to investigate the genetic causes of brain tumors and to develop and test potential treatments. Dr. Holland points to a story that illustrates the continuum from discovery to clinical trials that will underlie the BTC's efforts.

In 2000 -- using mouse models created in his laboratory -- Dr. Holland demonstrated that a signaling pathway containing the kinase Akt was activated in human gliomas and contributed to regulating a critical process that leads to the formation of these tumors. This work built on earlier observations by investigators in other labs showing that the tumor suppressor gene PTEN was frequently mutated in gliomas, and that the Akt pathway was activated by the loss of PTEN. Dr. Holland's hypothesis that the activation of Akt was crucial for the formation of gliomas was confirmed by the modeling his laboratory did in mice.

Some time later, he and his colleagues were approached by a small pharmaceutical company that had a drug that appeared to work by blocking the Akt pathway. And today, Memorial Sloan-Kettering neuro-oncologist Andrew B. Lassman is leading a Phase II clinical trial of the drug against recurrent or progressive gliomas. In addition, Memorial Sloan-Kettering radiologist Michelle S. Bradbury is working to develop ways to image response to the drug in mouse models. "Here's an example of how we can move from the discovery of a target, through mouse modeling and preclinical studies, and into clinical trials in patients of an agent that may work against the target, in a rational attack on this disease," Dr. Holland said.

A recent recruit to Memorial Sloan-Kettering and the BTC from UCLA is Ingo Mellinghoff, a medical oncologist and member of the Human Oncology and Pathogenesis Program (HOPP) and the Department of Neurology in Memorial Hospital. Investigators appointed to HOPP work at the interface of the laboratory and the clinic.

(Top) A mouse with a brain tumor. The tumor has been engineered to emit light using the same gene that in fireflies causes their tails to light up.

(Bottom) The same mouse, after treatment (in this case, with radiation). The tumor has responded to treatment and the light has "turned off." This technique, known as bioluminescence imaging, allows investigators in Eric Holland's laboratory to obtain real-time readouts of a tumor's response to treatment noninvasively.

Dr. Mellinghoff has several areas of research interest, among them developing clinical trials targeted to individual patients with brain tumors, or small groups of patients whose tumors have similar characteristics.

Medical oncologist Ingo Mellinghoff

"This is a departure from traditional clinical drug development, which often does not consider the genetic heterogeneity of tumors within the same disease. New technologies have empowered us to look at tumor cells at incredibly high resolution, and we can now focus on molecular subgroups of tumors and evaluate drug effects on signaling networks within tumor tissue. What my colleagues and I will be doing is to get a much more detailed molecular view of each individual's brain tumor," Dr. Mellinghoff elaborated, "and then to ask the question, 'What is the Achilles heel in this particular tumor and what would be the drug to try?'" The emergence and integration of genomics into clinical practice has helped to drive this work.

"Looking at cancer as a genetic disease -- the ability to detect the presence or absence of specific mutations in tumors -- has allowed us to think about this sort of 'personalized medicine.'" Dr. Mellinghoff observed that to accomplish his goals requires very careful tumor sampling, "so our neurosurgeons will play a big role, as will the clinical trial expertise available at Memorial Sloan-Kettering."

In addition to his work in the laboratory, Dr. Mellinghoff sees patients one day a week. "Seeing patients is a most gratifying human experience, points you toward critical questions to be addressed in the laboratory, and builds strong relationships with other oncologists, surgeons, pathologists, and radiologists. This is what the BTC is all about: to attack the disease from many different directions and with many minds at work."

Memorial Sloan-Kettering already has a broad spectrum of ongoing clinical trials in brain tumors. The institution is a member of the North American Brain Tumor Consortium, a consortium devoted to early-phase clinical trials in patients with gliomas, sponsored by the National Cancer Institute (NCI), and is also a participant in several Radiation Therapy Oncology Group (RTOG) studies. The RTOG is a multi-institutional NCI-funded research group. Lauren E. Abrey, Vice Chairman and Director of Clinical Research for the Department of Neurology, has coordinated the brain tumor clinical trials effort to date and will continue to do so as the BTC evolves.

Lauren Abrey Vice Chairman and Director of Clinical Research for the Department of Neurology

"The BTC gives us an opportunity to develop even stronger links to our scientists, so we can take clinical trials more directly from some of the work going on in the laboratory that deserves to be tested in the clinic," commented Dr. Abrey. "The BTC provides a framework for a scientist to say, 'We have what we think is a great idea in my laboratory' and for a clinician to learn about such an idea and work with that scientist to develop a trial. The BTC will be an important catalyst for this sort of activity."

In 2007, the BTC awarded its first annual grants to six Memorial Sloan-Kettering basic science and clinical investigators who come from Memorial Hospital departments, including the Department of Radiology and the Department of Neurology, and Sloan-Kettering Institute programs, including the Molecular Biology Program and the Molecular Pharmacology and Chemistry Program. Investigators will pursue a range of research projects from basic science to clinically oriented imaging.

"To do all of this, you need a place like Memorial Sloan-Kettering," concluded Dr. Holland. "A center willing to provide strong institutional support and resources, and with the extraordinary depth and breadth of scientific and clinical talent that exists here."