Major Research Areas

This group's research is crucial for the understanding of cancer. The evidence that carcinogenesis reflects to a significant degree the loss or blockade of normal patterns of cellular development fuels the high priority given by Memorial Sloan-Kettering to this area of research.

This work addresses the molecular regulatory mechanisms controlling the development of tissues and organs, including brain, muscle, lymphocytes, blood cells, patterning in the early embryo, and the embryonic limb. The success of these studies depends on the use of sophisticated molecular technologies for the manipulation of genetic DNA sequences and the knock-out or introduction of novel genes into cells in order to test their roles in the developmental process.

Major projects include:

• immune-system response in fruit flies;
• the genes that control early mouse-embryo development;
• the use of genetic,
• cell biological,
• molecular and biochemical approaches to study the intrinsic factors and extrinsic signals that regulate mesoderm development in Drosophila;
• the role of Kit receptor tyrosine kinase in mouse development;
• the study of complex cell movements in mouse embryos;
• the study of limb development and neural tube formation in chickens, mice and bats.

This research area -- central to the concept of carcinogenesis and cancer cell biology as well as to emerging strategies for the control of cancer growth -- encompasses a vigorous program of investigation.

The major projects concern:

• growth factor- and oncogene-mediated signals for growth and cessation of growth,
• the intracellular signaling pathway for both positive and negative growth regulation,
• the enzymatic machinery engaged in DNA replication during cellular proliferation, and the molecular fine structure of proteins and protein-protein and protein/DNA interactions (as determined by x-ray crystallography and NMR spectroscopy) involved in the machinery that regulates cell growth.

The cell surface plays an active role in normal cell function and in the disorders that lead to cancer. Adhesive properties form the associative bonds between cells and between cells and connective tissue elements, and are critical elements in the proper development of tissues and organs. Failure of such interactions may contribute to the metastatic properties of certain cancers and to the loss of growth control inherent to malignancies. Researchers are studying integrins, their ligands, and the intracellular signal pathways associated with cellular adhesion organelles.

Some of the most important and productive work in this area is now being done in the context of cellular neurobiology, since the neurological system exploits highly sophisticated mechanisms for the "wiring" of neurons in the central and peripheral nervous systems. The cell surface and intracellular membrane systems also play critical roles in other important processes, such as cell growth and division, the secretion of hormones and growth factors, cell-to-cell signaling, the formation of nerve synapses, the immune response, and the folding and transport of newly made proteins.

As a consequence of broad advances in basic molecular and cellular immunology, the opportunities for exploiting immunological mechanisms for the detection and treatment of cancer have grown considerably. Our efforts focus on several aspects of clinical cancer immunology, including:

• immunocyte differentiation,
• immunologic diagnostics and therapeutics (including the design and testing of tumor vaccines),
• and transplantation biology, including histocompatibility research.

This is another area in which basic laboratory science and clinical research are converging rapidly to improve cancer risk determination through genetic studies of high-risk families. Accurate assessment of prognosis and responsiveness to therapy can be made by determining a tumor's "genetic profile"--that is, the pattern of expression of its cancer genes at the time of diagnosis. There are three key elements critical to research in this area. They are:

• The identification, through cell and molecular biology, of novel candidate genes with the potential to transform normal to neoplastic cells;
• The search, through the pedigrees of cancer-prone families, for genetic elements responsible for high cancer risk, and the identification of the genes in question;
• The application of these gene discoveries toward more accurate detection, identification, and prognostication, in order to determine the best course of treatment and the likelihood of success.

Virtually all scientific components of the Institute are contributing to this critical area of Memorial Sloan-Kettering responsibility. This is particularly true with respect to the identification of novel biological targets for the discovery and development of new therapeutic interventions.

With every advance in our understanding of the molecular mechanisms that distinguish malignant cell growth and function comes a new opportunity for devising a corrective strategy. These strategies bring to bear biological research (from any of the areas of focused research reviewed above), chemistry for the design and synthesis of candidate drugs, structural biology for the analysis and refinement of drug/target interactions, preclinical drug development and toxicology, and clinical investigation.

The study of the biological mechanisms of drug resistance, another area of focus at Memorial Sloan-Kettering, concentrates on devising methods to overcome this impediment to successful treatment. In order to enhance the effectiveness of cytotoxic agents, our scientists are designing methods for the delivery and activation of chemotherapeutic agents targeted to cancer sites. Finally, the science of innovative therapeutics is not limited to chemotherapy, but engages the combined effects of drugs, radiation, and biological strategies (including the use of growth factors and gene therapy) in order to enhance clinical effectiveness.

Sloan-Kettering Institute chemists work on a variety of projects, from designing new drugs to making vaccines to developing tools for understanding the fundamental processes in cells. This work includes:

• combining multiple antigens into a single molecule to produce more effective cancer vaccines;
• synthetically creating epothilones;
• designing drugs that bind to potential cancer therapy target hsp90;
• re-sensitizing drug-resistant bacteria;
• developing analog drugs for better therapeutics;
• and investigating diversity-oriented synthesis, synthesizing large collections of molecules, then screening those molecules for biological activity -- an activity accomplished by the ETC-funded High-Throughput Core Screening Facility.

Sloan-Kettering Institute researchers have employed x-ray crystallography to visualize the structure of the BRCA2 gene, showing how it normally interacts with DNA and other proteins to repair genetic damage. And, in turn, our structural biologists are working with our chemists to help them develop promising compounds. For instance, the antibiotic geldanamycin was based on the structural understanding of heat-shock protein 90 (HSPO90), a protein involved in many cancers.

Sloan-Kettering Institute's new Computational Biology Program will combine biological findings with computer algorithms to conduct biological research. The Program's researchers will build computer models that simulate biological processes from the molecular level up to the organism as a whole, then using these models to make useful predictions -- again, bridging the gap between the Memorial Sloan-Kettering's researchers and clinicians. Members of the Computational Biology Program are working with members of Memorial Sloan-Kettering Cancer Center's Genomics Core Laboratory to create a database to store the Center's massive cancer data collection -- one of the largest of its type in the world. The Genomics Core Laboratory is using microarrays to measure gene expression, developing, for instance, a new technique to help doctors distinguish the molecular differences among adult soft tissue sarcomas. Microarrays are also being used to elucidate how transforming growth factor-beta (TGF-) influences metastasis.