Research

Research Programs

Signal Transduction

Program Members | Research Highlights | Contacts

Human cancer results from genetic and epigenetic changes that affect key cellular processes. Most of these processes, including excessive cell division and attraction of blood vessels to growing tumors, are normally regulated by binding of hormones called growth factors and angiogenic factors to receptors at the cell surface. Activation of the receptors by the hormones, and the resulting cascade of changes inside the cells that determine whether the cells will divide or commit suicide, and also whether growing tumors are likely to invade other tissues and disseminate to form metastases, is called signal transduction. Not surprisingly, the majority of mutations and chromosomal changes that contribute to cancer development affect these same pathways and processes. Thus, elucidation of signal transduction is vital for understanding how cancer arises in each individual, and the features that distinguish benign from aggressive cancers. Most importantly, components of the cellular machinery that mediates receptor-regulated growth processes are among the best rational cancer therapeutic targets in cancer.

Most of the new generation of targeted cancer therapies work by attacking this machinery. The first drug targeting a cancer gene product, Herceptin, is helpful for many breast cancer patients with tumors driven by the target hormone receptor, HER2. Chronic myelogenous leukemia (CML) is caused by activation of the signaling protein Abl, and is treated successfully with the new drug Gleevec. Gleevec is also effective for the treatment of gastrointestinal stromal tumors (GIST) because it blocks the hormone receptor Kit that often causes this disease.  Other drugs in clinical use include Tarceva, Erbitux, and Sutent (SU11248), which block hormone receptors, and a growing number of drugs including Velcade and Sorafenib that target the molecular machinery that responds to these hormones.

Despite continuing success in this area, much remains to be learned. Laboratories in the Signal Transduction Research Program are investigating how these signaling systems regulate cancer stem cells, communication of cancer cells with their tissue environment, and how they affect cancer invasion and survival of metastatic cells in foreign tissues. An important practical goal is the development of the best methods for matching patients with the appropriate cancer drugs for “personalized medicine.”  Each cancer develops in its own idiosyncratic manner, so that different signaling pathways are dysregulated in each cancer. So, the challenge is to match patients to the drugs that will have the greatest impact on the pathways affected in their own disease.

Program Members

David F. Stern, PhD, Program Co-Director, Associate Scientific Director, Yale Cancer Center, Professor of Pathology

Joseph Schlessinger, PhD, Program Co-Director, William Prusoff Professor
and Chairman of Pharmacology

Anton Bennett, PhD, Associate Professor of Pharmacology

Titus Boggon, PhD, Assistant Professor of Pharmacology

David Calderwood, PhD, Assistant Professor of Pharmacology

Lloyd Cantley, MD, Associate Professor of Internal Medicine, and Cellular
and Molecular Physiology

Lynn Cooley, PhD, Professor of Genetics and Cell Biology

Pietro De Camilli, MD, Eugene Higgins Professor of Cell Biology

Michael DiGiovanna, MD, PhD, Associate Professor of Internal Medicine (Medical Oncology) and Pharmacology

Patrick Gallagher, MD, Associate Professor of Pediatrics

Anthony Koleske, PhD, Associate Professor of Molecular Biophysics & Biochemistry
and Neurobiology

Joseph Madri, MD, PhD, Professor of Pathology

Nita Maihle, PhD, Professor of Obstetrics & Gynecology and Reproductive Sciences, Pathology, and Pharmacology

Jon Morrow, MD, PhD, Chairman and Raymond Yesner of Pathology; Molecular, Cellular
and Developmental Biology

Mark Mooseker, PhD, Professor of Molecular, Cellular, and Developmental Biology; Pathology

Jill Reiter, PhD, Assistant Professor of Obstetrics & Gynecology and Reproductive Sciences

David Rimm, MD, PhD, Associate Professor of Pathology

Mark Solomon, PhD, Professor of Molecular Biophysics & Biochemistry

Derek Toomre, PhD, Assistant Professor of Cell Biology

Benjamin Turk, PhD, Assistant Professor of Pharmacology

John Wysolmerski, MD, Associate Professor of Internal Medicine

Research Highlights

• Discovery of connections among multiple hormone receptor systems (ErbBs, IGF1 receptor, and Met) that has impact on use of drugs targeting these receptors for lung and breast cancer (Drs. DiGiovanna and Stern). Dr. Stern also elucidated much of the biology leading to development of Herceptin for treatment of breast cancer.
• Development of a new anti-cancer drug (now in clinical trials) targeted at the Raf signaling protein, important in melanoma and many other cancers (Dr. Schlessinger).  Dr. Schlessinger also developed the drug Sutent, now in use for renal cell carcinoma and GIST.  Much of our fundamental understanding of how receptors regulate cell growth is based on Dr. Schlessinger’s work.
• Elucidation of the three-dimensional structure of the receptor Kit, leading to a new approach to targeting this receptor and its relatives (Dr. Schlessinger). Dr. Boggon is using a related approach to study an important group of receptor-activated proteins known as JAKs.
• Models for regulation of cell migration through effects on the cellular skeleton network by Abl and Arg proteins, leading to new ideas about treatment of breast cancer (Dr. Koleske). Drs. Mooseker, Cooley, and Calderwood are working on related processes.
• Understanding the functional interactions between bone and breast tissues that clarifies breast cancer metatastasis to bone, and the cause of  microcalcifications in breast tissue (Dr. Wysolmerski).
• Development of new image analysis and computational approaches for biomarker analysis in tissue microarrays, with practical implications for personalized cancer therapies in several diseases including breast cancer and melanoma (Drs. Rimm, Maihle, Reiter).
• Development of new microscopic techniques for studying changes in the cytoskeleton in living cells, a powerful approach for studying processes including migration and invasion as they happen (Dr. Toomre).
• Elucidation of how cell surface proteins modulate formation of blood vessels, important for development of the blood supply for tumors (Dr. Madri).
• Integrated analysis of signaling networks mediated by protein kinases (Dr. Turk) and their antagonists (Dr. Bennett) that are central to activity of these signaling pathways and are major therapeutic targets.
• Drs. DeCamilli studies processes that modulate the transport and suppression of activated signaling proteins, which themselves represent a new area of therapeutic opportunities.

Contacts
Joseph Schlessinger, PhD, Program Co-Director
(203) 785-7395
joseph.schlessinger@yale.edu

David Stern, PhD, Program Co-Director
(203) 785-4832
df.stern@yale.edu