On October 7 and 8, leading scientists from across the U.S. gathered in Burlington to present their latest research advances in laboratory science relevant to cancer prevention, diagnosis, and treatment. Entitled "The Course of Cancer: From Transformation to Treatment," VCC's 19th Regional Cancer Research Symposium was held at the Wyndham Hotel & Conference Center and attracted over 100 researchers, clinicians, and postdoctoral, predoctoral, and graduate student trainees.
The Symposium, which was supported in part by the Lake Champlain Cancer Research Organization, a private philanthropy based in Hudson Falls, New York that has supported VCC for over 25 years, focused on four themes: Initiation & Transformation; Growth, Spread, & Metastasis; Host/Tumor Interactions; and Incidence & Therapeutics. Two sessions for competitive research poster presentations rounded out the program.
Alan Howe, PhD, assistant professor of pharmacology and co-chair of the Symposium together with his colleague, Russell Hovey, PhD, assistant professor of animal science, said the event had more than fulfilled the chairs' expectations.
"The absolute vanguards in the field of cancer have begun to think that taking a more holistic approach to cancer diagnosis and treatment is the way of the future. This concept significantly influenced Dr. Hovey and me in developing this Symposium," said Howe. "Though we did not specifically communicate it to each of the speakers, it ended up being a recurring a theme. The Symposium illustrated that in trying to determine why a person develops cancer, scientists have been thinking too simplistically in recent decades. They are now beginning to appreciate that genetic changes and the acquired capabilities they impart to cancer cells are all influenced by many modifying factors—at the genetic, cellular, organismal, and environmental level. These modifiers of disease progression include other predisposing genetic factors, tumor microenvironment, immune system function, as well as diet and other lifestyle factors. It became even clearer that specific changes that happen at every step along the course of cancer end up defining the characteristics of each individual's end disease."
Joanna Groden, PhD, of the University of Cincinnati set the stage for the Symposium by describing her work focused on the identification and characterization of two human disease genes that predispose individuals to colon cancer: APC (the gene associated with adenomatous polyposis coli) and BLM (the gene associated with Bloom's syndrome). While just 20% of colon cancers are hereditary, Groden explained that studying these cancers can provide a better understanding of non-inherited colon cancers. In order to get her insights to human colon cancer, Groden has developed mouse models.
According to VCC member and and Symposium attendee Marc Greenblatt, MD, "One of the most interesting things Dr. Groden talked about was her plans to take mice with mutations in the BLM gene that cause chromosome breakage in Bloom's Syndrome and cross them with mice carrying mutations in the APC gene. This might be a good model for studying how colon cancer develops in humans, because the chromosome breakage pattern scientists see in all Bloom's cells is the same kind they see in colon cancer cells. If we could identify the specific events that take place when there is chromosomal instability and APC abnormalities, which is the case in the majority of colon cancers, we could start to design therapies to reverse it."
Also speaking in the "Initiation & Transformation" program segment was Richard Pestell, MD, PhD, of the Lombardi Comprehensive Cancer Center, who spoke about his work on the role of acetylation of androgen and estrogen receptors in hormone-responsive cancers.
"Uncontrolled cell growth isn't the only factor in tumor invasion," said Alan Wells, MD, DMS, of the University of Pittsburgh. "Growth factor-induced motility is key." Wells went on to explain that tumor invasion requires the cell to at least partially dissociate from the primary tumor mass, overcome a matrix barrier, and survive and proliferate in a foreign environment.
One way this occurs, Wells said, is through the upregulation of autocrine signaling through receptors with intrinsic tyrosine kinase activity: the receptor most often involved is the EGFR/HER1/erbB1. Wells' research, using prostate cancer cell lines as a model, showed that activation of this receptor leads to down-regulation of the intercellular adhesion molecule E-cadherin, enabling the tumor cell to undergo an epithelial-to-mesenchymal transition. Following this transition, EGFR-mediated motility becomes a major driver of tumor invasiveness both in vitro and in vivo. Wells said that a better understanding of the key molecular switches that control steps in invasion will help researchers uncover novel targets for therapeutics aimed at limiting tumor motility and, ultimately, dissemination. Arthur Mercurio, PhD, of Harvard Medical School, elaborated on the epithelial-to-mesenchymal transition introduced by Wells.
Glenn Merlino, PhD, of the National Cancer Institute rounded out the segment, with a presentation on "Metastasis in Pediatric Sarcoma: What the Mouse Can Teach Us." Merlino's work is focused on rhabdomyosarcoma (RMS). Although the most common soft-tissue sarcoma in children, little is known about the molecular events or pathways associated with the disease, and prognosis for patients is poor. Using transgenic mouse models, Merlino and his colleagues have defined important roles for the Ink4a/Arf tumor suppressor locus and hepatocyte growth factor in the development of RMS. Merlino also spoke of his group's recent efforts to use these models to identify metastatic factors for RMS.
Valerie Weaver, PhD, of the University of Pennsylvania, spoke on the importance of the tissue microenvironment or extracellular matrix (ECM) in the regulation of tumors. "Each cell type-whether it be mammary epithelial cell, neuronal cell, or cancer cell-has a unique response to the ECM," Weaver stressed. Weaver went on to explain her research focused on the "tensional forces" created by small GTPases such as Rho and Rac in tumors. She has found that when such activity is inhibited, the tensional forces are repressed, and integrin activity and composition are normalized. She also spoke about the stiffness of the ECM and how increased degrees of stiffness in this environment from surgery, for example, might influence tumor recurrence. Weaver's work made clear the concept that epigenetic factors-in this case, the architecture of the surrounding stroma-exert a profound influence on tumor progression.
Scott Abrams, PhD, of the National Cancer Institute, discussed the importance of the complex interactions between the cellular immune system and cancer-stating that an improved understanding of the mechanisms by which CD8+ cytotoxic T lymphocytes (CTL) mediate antitumor activity in vivo may have important implications for the design of immunotherapies against neoplastic progression. Abrams' laboratory has been testing the hypothesis that the Fas/Fas ligand (FasL) system, utilized by antigen (Ag)-specific CTL, may play an important role in CTL-mediated tumor regression in vivo. CTL-mediated destruction of Fas-expressing tumor cells in vivo may function as an integral effector mechanism for the control of neoplastic development, growth, and spread. However, the process of tumor eradication by Fas/FasL interactions per se may also impart an immunity-based selective pressure. Specifically, cells resistant to Fas-mediated cell death may escape this mechanism of eradication. Thus, a second major aspect of his work has focused on potential negative contributions of this apoptotic system, in serving as a novel mechanism for increasing metastatic ability by driving tumor escape of Fas-resistant subpopulations.
Jessie Au, PharmD, PhD, of Ohio State University, presented a very provocative talk-quickly capturing attendees attention by declaring at the outset that although the nation spent billions of dollars on developing new drugs in a recent eight-year time period, only 6% of the test agents showed benefits in patients. Au's dismay with this costly and inefficient state of clinical trial drug development is the basis for her research exemplifying a true paradigm shift in ways of developing cancer therapeutics.
One of Au's recent projects involved the development of a new therapy for bladder cancer that has proved to be nearly twice as effective as the standard treatment. One of the premises driving the project was the goal of developing a drug-delivery based approach to treatment—one that would take into consideration the pharmacodynamic/ pharmacokinetic variability in patients resulting from physiological differences such as urine pH, volume, and production rate. Since all of these factors can be manipulated in a patient, Au next set out to determine the best treatment using computer simulations of bladder wall exposure and treatment effect to calculate response rate. Through this computational approach, Au was permitted to do something truly out-of-the-box in clinical oncology: rationally change multiple treatment parameters at one time. The approach provided results showing exactly what the best delivery treatment was in terms of dose, duration of treatment, pH level, and other factors.
"There are simply not enough patients to go around to support trials to test one treatment parameter at a time," said Au. "It's critical that we look at new ways of doing clinical trial design. For a relatively low cost, this project has provided the justification for a Phase III trial."
Graham Colditz, DrPH, MD, of Harvard University presented overwhelming evidence based on consistent epidemiological finding across a large number of well-designed studies that lifestyle factors are linked to the development of more than half of all cancers. Colditz cited tobacco, diet, alcohol, physical activity, and obesity as major behavioral risk factors. With tobacco's role in cancer development not being in question, Colditz focused on the two modifiable risk factors for which evidence of links to cancer is most convincing: obesity and physical activity.
Colditz discussed strong findings that demonstrate an association between greater body mass index (a commonly-used height/weight ratio), higher estrogen levels, and increased risk for breast cancer. According to several other studies cited by Colditz, body mass index is also a factor in increased risk for endometrial, esophageal, pancreas, kidney, and colon cancers.
With respect to physical activity, Colditz explained that data from 12 studies suggested that activity levels in women correlate with lifetime exposure to endogenous ovarian hormones, lowering cancer risk. He went on to review the findings of over 40 studies addressing physical activity in colon cancer; the researchers consistently observed a decreased risk with higher activity levels. Colditz said that the biological mechanisms at play in this correlation are likely that increased physical activity decreases insulin level, down regulates IGF, and changes prostaglandin E2 levels-all factors associated with cancer risk.
Keynote and J. Walter Juckett Distinguished Lecturer V. Craig Jordan, OBE, PhD, DSc, of the Robert H. Lurie Comprehensive Cancer Center, closed the Symposium with a very entertaining and informative session entitled "The Evolution of Resistance to Tamoxifen, Raloxifene, and Aromatase Inhibitors." Just prior to Jordan's session, Floyd Rourke, chairman of the LCCRO board of directors, presented brief remarks about J. Walter Juckett, the LCCRO founder commemorated by the Lectureship, as well about the VCC-LCCRO partnership.
Overall, the Symposium illustrated that cancer researchers and physicians will have to be more focused on getting a complete picture of each individual's cancer. Howe said, "The concept of patients getting a diagnosis and treatment plan that is specific to both the individual and the individual disease may not be far off. What we think of as diagnosis and treatment today will most likely be archaic in ten years or so. In the future, treating one person's colon cancer will not at all be like treating someone else's colon cancer."