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Specific Simple Models to Clinical Disease

November 7–10, 1996

Chaired By

 Richard Klausner, MD of National Cancer Institute

Meeting Description

Sessions:

  1. Overview, Ras in Budding Yeast, p53 Function
  2. Drugs Against Ras, Oncolytic Viruses, p53 in Pediatric Leukemias
  3. Cell Death (Anti-Apoptotic Proteins, Apoptotic Signaling, Mismatch Repair) HPNCC
  4. Metastases (TGF, VHL, Angiogenesis and Tumor Metastases), Summation

During the last decade the genetic basis for cancer has become increasingly better defined. Specific defects in the molecular controls that govern the cell progression through its cycle of DNA synthesis and cell division can result in a cancer cell. One of the remarkable discoveries that has accompanied the unraveling of the molecular “checkpoints” that determine whether it is safe for a cell to divide or not has been the observation that many of these molecular controls have been conserved throughout evolution. That is, many of the same molecular switches that regulate the genetic machinery of a human cell can be found in simple organisms like yeast. Not only is this of interest in its own right, but it offers the prospect for improving our understanding about the fundamental control mechanisms and defects that impact on human cells through the study of simpler organisms. By studying simpler organisms it may be possible to examine molecular events that might be less apparent or more difficult to unravel in human cells. Importantly, it may also be possible to utilize natural or induced genetic defects (i.e. mutations) in simpler organisms (e.g. yeast cells) to screen for drugs or agents that might take advantage of specific lesions and which might be used to treat human malignancies bearing similar genetic defects. Thus, the study of simple disease models offers potential for impact on the understanding and treatment of human cancer.

The Forum focused on discussions of selected important gene products that play critical roles in the life cycle of a cell (e.g., Rb, p53, Bc12, ATM) and considered the role of these important genes in both simple models and human disease. Experts in the study of simple models and human disease compared insights and findings with the hope that basic and clinical scientists would forge new insights and enhanced communications.

Meeting Summary

The future of cancer medicine lies in the development of highly specific strategies which lead to the selective destroying of tumor cells. This is in contrast to many current cancer therapies that target multiplying (i.e. proliferating) cells, and also results in the non-specific destruction of normal cells. Treatment for many childhood malignancies and a number of adult cancers are highly effective but there is a price to pay; either general toxicity or damage to normal organs within the body.

To begin to address the goal of selective cancer therapy we have to understand the differences between normal cells and tumor cells. If we can identify the machinery which is either selectively used or functioning incorrectly in the cancer cell it could bring new insights into how to destroy malignant cells. This was the theme of the 1996 forum.

The major problem in cancer is an alteration in the genetic machinery that controls cell growth development and death. Cancers by definition are cells growing in an uncontrolled fashion in the host and it is this loss of control which leads to problems. If we fully understood the pathways which control normal cell division we would be able to identify what goes wrong in malignant cells. Many groups throughout the world are working on this problem in the hope that we will be able to develop new chemicals to intervene selectively in the growth pattern of cancer cells. Approximately half of the speakers of the 1996 conference addressed topics which are pertinent to this area of research. Others discussed alternative strategies that may provide equally valid targets for therapy in the future.

Dr. Fink, Director of the Whitehead Institute at MIT presented his work on Ras, a protein that stands at the gateway of at least one major control pathway within the cell. This protein is present in normal cells, but if a single error in this structure occurs (a mutation) it can lead to the transformation of cells and this malignancy. Dr. Fink’s presentation focused on the function of the Ras protein in yeast, relevant because many of the important pathways which function in human cells can be found in simpler organisms and these can be readily manipulated in the laboratory.

Dr. Oliff, Director of Cancer Research at Merck laboratories, indicated that several different drugs have been identified which interfere with the maturation of the Ras protein as it is processed from a precursor molecule to an active protein within the cell. He also discussed cost benefit implications underlying the relatively slow introduction of new therapeutic strategies into the clinic. Dr. Kolodner from the Dana-Farber Cancer Institute presented work that uses yeast to elucidate mechanisms by which cells can repair errors in DNA. Studies such as those presented by Dr. Kolodner are fundamental to our understanding of the control of cell division and how this may go wrong in cancer cells.

Dr. S. Markowitz, Case Western Reserve University, discussed inactivation of DNA repair genes in different forms of colon carcinoma. Loss of function of these genes can increase the rate of mutations in DNA by over 100 fold. He indicated that in over 90% of colon cancer studied, which have defective DNA repair enzymes, another defect can be identified in a receptor for a growth factor called TGF-normally a ‘tumor suppressor’. When the protein is expressed in a defective form, this can lead to tumor growth. Dr. Markowitz defined specific questions which need answering to substantiate these discoveries.

Probably the most investigated protein within cancer cells over the last decade is p53 which functions like a brake cell, slowing down cell division. If errors occur in the duplication of DNA during cell division it is thought that p53 can slow the process down to give the cell sufficient time to repair the damaged DNA. Mutations or errors are present in the DNA coding for the p53 protein in many tumor types. Dr. Levine, Chairman of the Department of Molecular Biology at Princeton University, has been studying the parts of the p53 protein which interact with the pathways controlling cell division. If these can be identified accurately it may be possible to replace all or part of the molecule with the one which functions properly. For example, Professor Lane, Department of Biochemistry at the University of Dundee in Scotland (unable to attend the meeting) has been working on the development of synthetic regions of the p53 molecule which can mimic the activity of the whole protein. Administration of these to patients could represent one therapeutic strategy to repairing aberrant p53 protein functions. Dr. Felix from the Division of Oncology, Philadelphia Children’s Hospital, presented a hypothesis that even the normal p53 protein may play a role in the development of childhood leukemias.

There are many different approaches to using “gene therapy” for cancer; one of the simplest being to replace a defective gene in the cancer cell with the correct version engineered in the laboratory. Whilst we are in a position to manufacture such genes, the problem of delivery is formidable. Dr. Kirn, Director of clinical research at Onyx Pharmaceuticals, showed some intriguing data using a modified virus that has been engineered in the laboratory to only divide in cells which contain a defective p53 protein (i.e. cancer cells). Division of the virus leads to lysis of the infected cell, hence the tumor is eradicated. Dr. Kirn indicated that clinical trials had begun, but it was far too early to predict its effectiveness. Another approach to defining suitable targets for the development of cancer therapy is to study apoptosis – the way in which normal and abnormal cells die. It has been suggested that a block in the pathways by which cells enter apoptosis can lead to the accumulation of malfunctioning proteins.

Dr. Craig Thompson, Howard Hughes Medical Institute, University of Chicago, presented studies which indicate that the apoptotic mechanisms may play a role in eliminating cells which fail to complete DNA replication in a statutory fashion. Apoptosis is blocked in cells which express a protein called Bcl-xL and he believes Bcl-xL and the p53 protein function in cells to potentially contribute to genetic instability. Dr. Fuks, Chairman of the Department of Radiation Oncology at Memorial Sloan-Kettering Cancer Center, believes that in normal cells the apoptotic mechanism is very tightly controlled. He presented experimental data to suggest ways in which this control might be loosened in tumor cells which could enhance their sensitivity to radiation and thus bring about apoptotic cell death. Dr. Klausner, Director of the National Cancer Institute, developed an elegant argument to show that another “tumor suppressor” gene may play a role in the development of a form of kidney cancer. This gene, called VHL, was identified in 1993 and is known to be responsible for an inherited cancer syndrome called von Hipple-Lindau Disease. Dr. Klausner is currently investigating the function of the protein coded for by the VHL gene. Once this has been identified it will be possible to understand how the molecule fits into the overall physiology of the cell.

A completely different way of attacking tumors was presented by Dr. Lynn Matrisan from the Department of Cell Biology at Vanderbilt University. A group of proteins called the metalloproteases have been shown to be produced by tumors. These proteins are capable of attacking the ‘glue’ which sticks cells together, potentially permitting cancer cells to spread to different sites within the body. Dr. Matrisian presented data to show how one particular protein called matrilysin (did she name it?) is expressed in breast tumors and indicates ways in which inhibitors of the family of proteins may prevent tumor spread within the body. Dr. Folkman from the Division of Pediatric Surgery, Boston Children’s Hospital, discovered that tumors produce angiogenic factors which encourage the growth of blood vessels into solid tumor deposits. Inhibition of these angiogenic molecules should prevent vascular invasion of the mass and the tumor should starve to death. This leads into the theme of the 1998 conference: understanding the relationship between tumors and their blood supply.

The 1996 conference was one of the most successful we have ever had. I am sure that as a result of the Forum, new collaborations and exchanges of ideas amongst the delegates will continue for the foreseeable future.

Quotes from Participants
“I thoroughly enjoyed the meeting. I hope everyone found it as informative and stimulating as I did.” - Richard D. Klausner, MD, Director, National Cancer Institute, Bethesda, MD

“My attendance will add new dimension to my work. The assembly of such fine scientists in the highly interactive sessions and unreserved discussions would otherwise not have happened. Indeed, my own informal conversations with leaders in the field will shape my lab experiments during the coming months. My first hand experience confirms the concept that this type of dialogue and communication is the only way to ultimately make faster progress in our care of patients.” -- Carolyn A. Felix, MD, Children’s Hospital of Philadelphia, Philadelphia, PA

“I cannot think of any scientific meeting I have attended that I so thoroughly enjoyed both personally and professionally. Your vision has created a unique event that truly does advance the fight against cancer. I found the Forbeck Symposium unique in both offering the opportunity for unusually frank scientific exchange and also in drawing together individuals from areas as diverse as basic science, pediatric and adult oncology, and radiation therapy, who suddenly discovered they have much to say to one another.” -- Sandy Markowitz, MD, Ph.D., Case Western Reserve University, Cleveland, OH

“…it was truly an exciting and enlightening experience to work with Dr. Klausner and the other scientists involved … a truly remarkable research forum.” -- David Kirn, MD, Onyx Pharmaceuticals, Richmond, CA

“The small group environment was an excellent setting for discussion and scientific exchange. I just sponsored a Cancer symposium at the Whitehead Institute. The format was quite different form yours. It was attended by 1200 graduate students and postdoctoral fellow … From both meetings came an important message – our current approaches are inadequate because we do not have the tools to examine what is key and what is just an epi-phenomenon. But there are exciting new technologies that will completely change both the diagnosis and the prognosis of cancer. These are in the laboratory now, but scientists, oncologists and venture capitalists all know that once these techniques are developed into practical applications there will be a radical change in the cancer field. The questions, the approaches, and the theories will all be affected by the ability to monitor all the genetic changes that take place in a cancer cell. Within five years our current symposia will seem prehistoric … Nothing will be the same … Perhaps you could consider these new technologies as a focus for one of your future meetings.” -- Gerald R. Fink, MD, Director, Whitehead Institute, Cambridge, MA

“I think in every way conceivable, this forum fulfilled all of the goals that we might have set, and that it fostered a spirit of dialogue, created excitement amount the participants and opened up, I am sure, new avenues of collaboration.” -- Philip A. Pizzo, MD, Children’s Hospital/Harvard Medical School, Boston, MA

“… having a child with such a terrible illness can at times make a parent feel helpless. The invitation to attend the meeting at Hilton head was rewarding on so many levels. It was a weekend filled with emotion, conviction and encouragement. I always measure commitment and success by what people do; not what they say. The William Guy Forbeck Foundation represents the best example I have seen of how a small, energized, dedicated group can make a difference in the fight against cancer.” -- Jim and Jennifer Buchanan, Peabody, MA

“Having Rick Klausner chairing your meeting was outstanding and I am particularly pleased to see Dr. Joe Laver joining your Board of Trustees.” -- Ernest “Fritz” Hollings, US Senate, Washington, DC (Board of Trustees)

Forum Participants

Rachel Altura, MD
Rhode Island Hospital
 Forbeck Scholar

Carolyn A. Felix, MD
Children's Hospital of Philadelphia

Judah Folkman, MD
Harvard Medical School

Zvi Fuks, MD
Memorial Sloan Kettering Cancer Center

David H. Kirn, MD
Onyx Pharmaceuticals

Richard Klausner, MD
National Cancer Institute

Richard D. Kolodner, PhD
Dana-Farber Cancer Institute

Arnold J. Levine, PhD
Princeton University

Sanford Markowitz, MD, PhD
Case Western Reserve University

Lynn M. Mastrisian, PhD
Vanderbilt University Medical Center

Allen I. Oliff
Merck Research Laboratories

Julie Park, MD
Seattle Children's Hospital
 Forbeck Scholar

Craig Thompson, MD
Howard Hughes Medical Institute