Chromosomal Instability & Aneuploidy

The 2016 Forbeck Foundation meeting provided an exciting venue for researchers in different fields to come together, for the first time, to discuss new advances in understanding the structure of cancer genomes, with potentially important implications for novel therapeutic strategies in cancer. Much like the evolution of a new organism, cancer genomes evolve from normal ones by a series of DNA alterations, enabling all of the manifestations of the disease to develop. It is common to quote Shakespeare’s Tempest for the insight that “What’s past is prologue;” this insight was the theme of the 2016 Forbeck meeting. Knowing the past history of a cancer genome can help us identify the “drivers” of uncontrolled cancer cell division. Such drivers are important drug targets. Knowledge of the evolutionary history can also tell us about trade-offs made during cancer evolution, trade-offs that could lead vulnerabilities that might also be “druggable.”

Immunotherapy

The 2015 Forum was focused on Cancer Immunotherapy. Major topics of the forum included (i) cellular therapies using antigen specific and gene-modification T cells for targeting leukemia and solid tumors; (ii) overcoming hurdles and barriers with regard to immunogenicity, immune escape, and the role of tumor microenvironment; (iii) vaccine strategies and antigen presentation; (iv) the role of immune cells in allogeneic transplantation; and (v) current antibody/combination approaches for the treatment of pediatric malignancies. During the past decade, major advances have been made in improving the efficacy of these modalities and regulatory hurdles have been taken. Nevertheless, there is still a long way to go to fully exploit potential of immunotherapeutic strategies to improve the cure of children and adolescents with malignancies. This forum supported new collaborations and insights for further translational and clinical immunotherapy studies.

Invasion & Metastasis

Most cancer deaths are due to metastasis – the spread of cancer from its site of origin to distant, vital organs, and the physiological damage caused by tumor growth in those organs. While the broad outlines of the process of metastatic spread are known, much of the details of the process remain poorly understood. To continue to improve cancer survival rates, we must face and tackle the problems inherent to metastatic disease. Cancers that are detected early, before they are believed to have spread to other organs, are generally treated with more success than cancers that are metastatic at diagnosis. However, even cancers that are detected early will recur in some patients, but our ability to predict which individuals will have recurrences is limited. Thus, adjuvant therapy is often given to patients with early stage disease who are believed as a group to be risk for recurrence, leading to over-treatment of some patients to benefit a subset of them. Some recurrences can occur years or even decades after apparently successful primary treatment, and research on tumor dormancy is providing insights into these delayed recurrences.

Resistance Mechanisms

Cancer therapies that specifically target the genetic alterations associated with subsets of advanced cancers have shown impressive success in the clinic.  Examples include ABL inhibitors for chronic myelogenous leukemia, RAF inhibitors for BRAF mutant melanomas, EGFR inhibitors for EGFR mutant lung cancers, and HER2 inhibitors for HER2 amplified breast cancers. In each of these cancer paradigms, the treatments are often highly effective, leading to remarkable remissions that have a profound beneficial impact on patients. These successes have changed the landscape of the diagnosis and treatment of cancer for the foreseeable future.

Tumour Metabolism

Oncogenic events that convert normal cells into cancer cells promote cell growth and proliferation and inactivate checkpoints that would normally block these functions in the absence of sufficient growth factor, oxygen and nutrient availability. Other oncogenic events block cell death, induce tumor vascularization, and promote genetic instability that accelerates tumor progression. Tumor cells also rewire metabolism to increase nutrient uptake, to produce building blocks for new cells, and to sustain energy homeostasis in stress and with the high metabolic demand of cell growth and proliferation. This distinct metabolism of cancer cells has been known for decades, and was first highlighted by Otto Warburg who found that cancer cells undergo aerobic glycolysis.  This was termed the “Warburg effect” and is the basis for current FDG-PET imaging of tumors. Furthermore, clinically important anticancer agents include inhibitors of cellular metabolic pathways (e.g., antifolates, the thymidylate synthase inhibitor 5FU, the nucleoside analog gemcitabine). Despite this, until recently cancer metabolism was an area of little research.

Epigenetics

Cancer development is a multi-step process with mutations in proto-oncogenes and tumor suppressor genes playing a well-defined role.  In this regard, cancer is a genetic disease. However, cellular mechanisms that control the differentiation state, survival and self-renewal of cancer cells are often independent of mutations in DNA sequence and are increasingly recognized as critical for tumor development and progression. These epigenetic mechanisms are largely a result of the multitude of chromatin modifications that control gene expression. Since epigenetic changes are largely reversible, there is significant hope that therapies targeting these modifications may be particularly effective anti-tumor agents.

Cancer Genomics

The focus of the 2010 Forbeck Foundation was on the rapidly moving field of cancer genomics. It is generally accepted that cancer is caused by the accumulation of mutations or epigenetic modification that affect specific genes. The identity of the affected genes provides clues to the cellular processes underlying tumorigenesis and have proven useful for diagnostic and therapeutic purposes. To date, however, only a small fraction of the genes has been analyzed and the number and type of alterations responsible for the development of common tumor types are not well known. 

The Biology and Treatment of Primary Brain Tumors

The focus of the 2009 Forbeck Foundation meeting in Hilton Head was primary brain tumors.These are a leading cause of cancer death in children. Although their occurrence in adults is relatively rare, the tumors can be very aggressive with poor survival rates.

In adults, primary brain tumors usually arise in cells called astrocytes, which are thought of as the supporting cells of the nervous system. These cells, in their poorly differentiated form, can produce a tumor type called gliomas, which are exceedingly difficult to treat with any of the common approaches (surgery, chemotherapy, or radiation therapy). 

Immunotherapy and Breaking Tolerance

The 2008 Forbeck Symposium focused on new developments in cancer immunotherapy. Recent findings in tumor immunology have provided a clearer understanding of the complex interaction between the host immune system and cancer. Significant progress has been made in elucidating the function and regulation of immune cells, in identifying molecules that are expressed by tumor cells and can be targeted for immune-based therapy, and in understanding the mechanisms by which tolerance to self-antigens is maintained. These insights have resulted in a significant transformation in the field of tumor immunology over the past several years, and led to the development of novel therapies that are now yielding encouraging results in a subset of human cancers. 

MicroRNA and Cancer

The broad goal of the 2007 Forbeck Symposium was to examine the relationship between microRNAs and cancer. The past few years have seen a veritable revolution in biology, with the discovery that small RNAs act in a broad range of biological processes and pathways. In the expanding world of small RNAs, microRNAs hold a special place in that they are evolutionarily conserved regulators of gene expression networks. These ~18-22 nucleotide, single stranded RNAs are derived from fairly conventional genes, with the exception being that the end-product of the gene is a small, non-coding RNA rather than an encoded protein. Standard transcriptional regulatory circuits govern the synthesis of the primary microRNA transcript, which is then processed through two steps to yield a mature small RNA. These small RNAs join RISC, the core effector complex of the RNA interference (RNAi) pathway, associating specifically with an Argonaute protein. The Argonaute protein uses the small RNA as a guide to select silencing targets based upon sequence complementarity between the small RNA and a target messenger RNA. Through such interactions, each microRNA can regulate the expression of potentially hundreds of genes. While the human genome harbors 20- 30,000 protein-coding genes, microRNAs are numbered in the hundreds. However, this number, combined with broad target profiles, gives microRNAs potentially quite large roles in regulating the biology of an organism.

Stem Cells

The 2006 Forbeck Forum focused on a question that has captured the attention of cancer scientists and cancer research funding bodies around the world. Does every cell in a tumor, whether liquid (leukemia) or solid, have equal ability to sustain cancer growth or are some cells within the tumor more potent than others? The answer to this question has the potential to alter research approaches away from study- ing the cellular and molecular proper- ties of entire tumor tissue towards focusing on the tumor-initiating cells or so called cancer stem cells (CSC). There was much discussion at the Forum on the best nomenclature for these cells. Evidence is emerging that for many tumors, they are organized as cellular hierarchies that are sustained by stem- like cells in much the same way as normal organs. To gain a clearer picture of CSC and their similarities and differences to normal stem cells, the 2006 Forum assembled 12 leading stem cell scientists whose interests ranged from stem cell biology of lower organisms like Drosophila to blood and intestinal stem cells of the mouse, to normal human hematopoietic stem cells (HSC) and leukemic stem cells (LSC). The unifying theme of the Forum was that progress to identify and characterize CSC from different tumors and to under- stand their importance in cancer will only come when we understand how normal stem cells for each organ actually work. One field of study, normal or neoplastic, informs the other. Indeed by understanding the genetic and epigenetic programs that govern normal stem cells, we can begin to understand how the neoplastic process subverts normal stem and progenitor cells. This Forum showed once again the value in bring- ing together investigators from different stem cell areas that often do not talk to each other and having them focus their attention on one question. New research directions were formulated, collaborative research projects were developed, and ultimately a strategy for progress in this promising field was stimulated in each of the participants. 

Innovations in Imaging in Cancer Research

Both diagnosis and treatment of cancer have changed dramatically in the recent past, as research in animal models and patients has identified the molecular alterations that occur in the initiation and progression of many tumors. This new level of understanding has identified a myriad of targets for potential drugs designed to inhibit specific alterations in tumor cells, provided opportunities to stratify patients according to level of risk, and suggested methods to detect cancer earlier. In parallel, our ability to image functionally the molecular and biochemical changes that occur in tumors has advanced dramatically – both in patients and in animal cancer models. Magnetic resonance imaging (MRI) can identify previously undetectable lesions, positron emission tomography (PET) can utilize changes in tumor biochemistry to locate tumors and monitor their functional characteristics and optical imaging technologies (FRI, FMT) are at the verge of being introduced into clinical care to expand the realm of what the human eye can perceive. These technologies, coupled with other imaging modalities, have altered our ability to detect tumors, stage tumor progression, observe metastases, detect recurrences and rapidly monitor tumor responses (or lack of response) to alternative therapies. The development of small animal MRI and microPET instrumentation, and instrumentation for optical imaging of bio- luminescence and fluorescence, has brought non-invasive molecular imaging into the toolbox of researchers who study cancer in small animal models in which the mice are subject to extensive genetic manipulation.

Molecular Targets in Pediatric Malignancies

Several themes were developed during the course of the symposium. These included the concept of “oncogene addiction” in which a cancer cell becomes “addicted” to it’s mutant oncogene, rendering it susceptible to induction of cell death by oncogene inhibitors. The role of the microenvironment in supporting tumor cell growth, and as a target for therapy was discussed. In addition to targeting of kinases in cancer, such as BCR-ABL, the potential for targeting the apoptotic machinery of cancer cells was present- ed by several investigators.

DNA Damage & Cancer Susceptibility Syndromes

The important role that DNA dam- age plays in cancer development is illustrated by the clear connections between exposures to certain types of DNA damaging agents in the environment and the development of cancer, such as the links between cigarette smoking and lung cancer or sunlight exposure and skin cancer. In addition, the majority of inherited syndromes characterized to date that lead to increased cancer development in families result from inherited mutations in genes that are important for DNA damage responses.

Cellular Senescence and Cancer

This exciting and highly productive Forum focused on cellular senescence – a biological response governed by known cancer-relevant pathways and thought to be integral to the suppression of cancer and the response to anti-cancer agents. Investigators from diverse areas discussed the cellular senescence mechanism from the molecular, cellular and organismal perspectives. Numerous outstanding questions were discussed including:  Does senescence represent an effective mammalian tumor suppressor mechanism on one hand yet drives the age- related pathologies on the other? Are there species-specific differences in mice and humans or does this relate to experimental design? What role do telomeres plays in suppressing or fueling chromosomal instability and how does this influence the initiation and progress of cancer in the organism? What are the nature of the signals emanating from the telomere and how is this signal mediated by damage signaling pathways in normal and neoplastic cells? How is telomerase regulated? How do cellular senescence pathways influence the biological impact of oncogenic lesions such as Myc and can we forge a link to the core cell cycle machinery? A discussion of these issues generated more questions than answers and the level of discussion was so robust that most speakers found it challenging to get past the first few slides of their talk. 

Differentiation as Cancer Therapy

The Year 2001 Forum of the William Guy Forbeck Research Foundation dealt with the topic of Differentiation in Cancer Therapy.  While the concept 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.

Allogeneic Stem Cell Transplantation

The Year 2000 Forum of the William Guy Forbeck Research Foundation focused on the topic of allogeneic stem cell transplantation.  Participants included experts in stem cell biology, scientists interested in experimental models of transplantation and tumor immunology, clinical researchers, and population scientists.  The general mood of the meeting was one of considerable excitement and optimism.  This mood was created by the general agreement that for perhaps the first time we now have the necessary knowledge and most of the tools to harness the enormous power of the human immune system in the fight against cancer.

Targeting Gene Therapy - A Reality?

This was a very exciting and stimulating meeting devoted to basic and clinical research advances in gene therapy for the treatment of cancer.  Despite the recent unfortunate death due to gene therapy (of a patient without cancer) that has been widely discussed in the lay press the Forbeck meeting gave a very useful perspective on the current state of the art of this field.  From the results presented at this meeting it is possible to estimate that ~1,000 people in the world with cancer have received some form of gene therapy.  We can also conservatively estimate that 5-15% of these people have derived some benefit from this therapy.  A likely guess is that ~10 people have died possibly related to gene therapy (1% rate) and tests of other new therapies often have  mortality rates of 5-10%.  While we obviously don't want anyone harmed by gene therapy, these estimates tell us gene therapy is well within the range for possible benefits and side effects encountered in the development of other types of new cancer therapies.  Many different tumor types are being tested and these trials are mainly occurring in adults with children's trials to come later.

Angiogenesis And Accessibility

Dr. Folkman opened the meeting by sketching a list of 15 central questions and interesting problems in the field of angiogenesis research.  George Yancopoulos presented his discovery of a new family of angiogenesis stimulators, the angiopoietins.  He showed that angiopoietin-1 may work together with another angiogenic factor, VEGF to build normal new blood vessels in the embryo and possibly in wounds.  Furthermore, a related member of this family, angiopoietin-2 appears to be made by the endothelial cells which line the blood vessels coming into tumors.  Angiopoietin-2 appears to instruct new tumor vessels not to coat themselves with an outer layer of smooth muscle cells, as is the case for new vessels in wound.  This leaves tumor vessels with thin walls.  Dr. Yancopoulos made transgenic mice which over-produced angiopoietin-1 in their skin.  These mice produced extra vessels with large diameters, beneath the skin.  The mice had red Skin.  This proved that angiopoietin-1 is a new member of the family of angiogenic stimulators, but more importantly, the vessels did not leak blood or reveal microbleeding, as was the case with another angiogenic factor, VEGF

Second Malignancies

The XIIIth Forbeck Research Foundation Forum focused on the observation that secondary cancers can occur in patients, after they have been treated for their original malignancy.  This effect is particularly marked following the administration of particular combinations of cytotoxic drugs.  Most second malignancies are leukemias, and one of the groups of drugs known to cause these cancers is called "topoisomerase II inhibitors".  While the toxicity of these drugs is well recognized, they often form essential components of drug regiments used for the successful treatment of cancer.