Raymond Paul Warrell, Jr., MD, Genta Incorporated
While the concept of ‘Differentiation as Cancer Therapy’ has obviously evolved to reflect scientific advances, the general idea of differentiation goes back almost 100 years. Within this framework, cancer is viewed as a disease of relatively immature cells that are occasionally dividing at an accelerated rate, but whose major defect is a decrease in the rate of cell death. The imbalance of dividing cells versus dying cells results in tumor growth that ultimately overwhelms the patient. The relative longevity of cancer cells owes to their being trapped in a prolonged state of adolescence in which their ability to grow up is blocked due to genetic abnormalities. Conceivably, drugs that could eliminate this maturation block might enable these cells to grow up, grow old, and die off. Thus, treatments that reverse this dividing vs. dying imbalance- however slightly – should over time eventually extinguish the disease.
Leo Sachs, the Forum’s keynote speaker, provided an expansive view of cellular capabilities. The general proposition was that both normal and malignant cells were enormously “plastic”, an idea that implies cancer cells can be reprogrammed to behave normally. All cells communicate via networks of factors that are continually cross-talk. Dr. Sachs pointed out that simply because we do not yet know how to interfere does not mean that it cannot be done. Moreover, given their criticality, these pathways are likely to multiply redundant, and this “power of redundancy” will increase the likelihood of making chance observations that would yield major insights. Pier Paolo Pandolfi has created mouse models of several human diseases, particularly acute leukemias. Having focused on acute promyelocytic leukemia (APL), his group has genetically engineered mice that express proteins that are known to give rise to human leukemia. These models have yielded insights into both the cause and biology of leukemia, and they are being used to determine mechanisms of drug action, as well as targets for new treatments. Malcolm Moore presented information regarding self-renewal properties of hematopoietic stem cells (i.e., cells that continually give rise to new blood-forming cells). He described a number of factors that normally regulate this key process in healthy cells, along with those that deregulate the processes in cancers such as leukemia, lymphoma, and myelodysplasia.
Makio Ogawa then reviewed how these early cells make their own transition from the earliest stages of immaturity into adolescence, and also how these cells that are nominally “blood cells”, have been used to rebuild damaged liver tissue.
Following on these ideas, Calvin Harley discussed work in using such stem cells as a mechanism of novel gene discovery (so-called “pharmagenomics”), as well as a source of cells for transplantation or replacement therapy. This incredibly powerful technology could eventually be used to provide new nerve cells for patients with Parkinson’s disease or stroke, cardiac cells for patients with heart attacks, pancreas cells for patients with diabetes, and bone or muscle cells for patients with crippling diseases.
Gary Gilliland proposed a simplified grouping of the more than 100 gene mutations that are responsible for leukemia into two broad types: those that confer advantages with respect to increased cell division or prolonged survival, and those that impair differentiation. This concept then refines those methods of attack that can be targeted to these broad categories of disease. For example, Gleevec® would be viewed as a prototype drug useful for the first class, and retinoic acid or arsenic as drugs for the second class.
Daniel Tenen presented a somewhat different concept wherein several types of leukemia share abnormalities that center on disrupted differentiation. These abnormalities should be potentially reversible by targeting a specific gene product (known as C/EBP-_).
Phillip Koeffler then showed that addition of certain older drugs in a new sequence could reactivate many genes thought to be dormant in leukemias. Moreover, restoration of these normal gene functions could lead to extinction of the leukemic cells.
Stephen Baylin focused on novel approaches to solid tumors that similarly involve reactivation of normal genes that are abnormally shut down in cancer cells. This silencing is caused by specific chemical changes (known as methylation and acetylation), both of which can now be manipulated by drugs. Because of its potentially broad applicability to gene regulation, this area is one of the most exciting in biomedicine.
Finally, Scott Lippman closed the Forum by taking a macro view of these developments from a public health viewpoint, particularly focusing on translation of these ideas into very large (and long) trials of interventions for cancer prevention in large U.S. populations. He noted that the first generation of these approaches, which have included vitamin approaches, have been strikingly unsuccessful despite their intuitive attractiveness. Newer approaches, such as the use of Advil®-like drugs to prevent colon cancer in high-risk patients, have been considerably more promising. He suggested that future approaches to cancer prevention must first careful identify patient populations who are at highest risk, rather than attempting to broadly study healthy people with agents that need to be taken for decades in order to determine their benefit (or additive risks).
“It takes good people to attract good people”, and the high level of scientific quality in this year’s Forum reflected the world-class caliber of our speakers. We again saw very high enthusiasm for the Forum’s format by all participants. The idea of ‘differentiation therapy” has yielded several spectacular successes in the last 10 years. In 1992, APL was a lethal disease primarily in young adults, and less than 25% of patients survived. By the end of the decade, this leukemia had been transformed. A new patient with APL in 2002 should expect to be cured with greater than 85% probability. As Chair of the 2001 Forum, I speak for the excitement of all the attendees that this type of progress can only be accelerated in the future. I was honored to lead this group, and we are all most grateful to the Forbeck Foundation for continuing its sponsorship of this wonderful event.
Stephen B. Baylin, MD
Johns Hopkins Oncology Center
James R. Downing, MD
St Jude Children's Research Hospital
Gary Gilliland, MD, PhD
Howard Hughes Medical Institute
Calvin B. Harley
H. Philip Koeffler, MD
CLA School of Medicine
Scott M. Lippman, MD
MD Anderson Cancer Center
Malcolm A. S. Moore, D.Phil
Memorial Sloan Kettering Cancer Center
Makio Ogawa, MD, PhD
Medical University of South Carolina
Pier Paolo Pandolfi, MD
Memorial Sloan Kettering Cancer Center
Weizmann Institute of Science
Daniel G. Tenen, MD
Harvard Institutes of Medicine
David Tuveson, MD, PhD
Dana-Farber Cancer Institute
Raymond Paul Warrell, Jr., MD
We are reliant on drug therapy for the treatment of the majority of cancers that have spread throughout the body. Many of these agents have been in existence for many years and in general the drugs work by killing rapidly dividing cells within the body. This means that the drugs damage both cancer cells and normal cells in the body that are also rapidly dividing. This is why blood counts fall and hair falls out after patients receive certain types of cancer drugs. A major goal of researchers within both academia and the pharmaceutical industry is to find effective ways of stopping cancer cells in their tracks without major side effects. This is becoming increasingly realistic as we understand more and more about how normal and cancer cells work. Cancer cells are so dangerous simply because they divide so rapidly. If this could be prevented and the cells could be brought back under control again then this would elicit an effective therapy. One way to achieve this is to use drugs that can make the cancer cells differentiate into an end type non-dividing cells that no longer have the capacity to divide. This is becoming a possibility for several cancers. Furthermore, we are gaining considerable insights into precisely how these agents work. Bringing together a group of scientists studying how these differentiation agents affect cells and the oncologists who use them in the clinic should lead to a greater understanding of the demands of both parties.