FUTURE PLANS
The major cutting-edge themes of the CGS Program have developed considerable momentum since the last review. We will continue the maturation of the established research areas towards application to human cancer. Regarding the regulation of cell proliferation by vitamin D and soy, we can look forward to substantial progress in elucidating the molecular mechanisms involved in the vitamin D-soy synergism with the recent funding of Dr. Cramer’s R01 in this area. The major next step will be the development of additional clinical trials and epidemiological studies to determine the impact of these dietary factors on prostate and breast cancer. These clinical trials are currently in the planning stage with members of the Clinical Research Program, headed by Dr. Peter Clark, and will be the subject of future applications for funding. We can also look forward to the results of Dr. Cline’s R03 award on the effects of dietary soy on biomarkers in human prostate cancer to develop future research in the bench to bedside direction, to determine the cellular and molecular mechanisms involved. This will also be strengthened by future research in the nonhuman primate models that Dr. Cline has developed in his R01 on the interactions of soy and estrogen in the breast.
Research on the role of dietary lipids in regulating cancer cell proliferation and metastasis is clearly ripe for development of collaborative funding such as a P01 application or a series of inter-related R01s among the investigators involved. Future research on n-3 versus n-6 PUFAs will involve additional mechanistic studies to identify the most relevant lipid derivatives, and their mechanisms of signaling. In addition, there is an obvious translational direction to this research in terms of developing new dietary interventions. This research also has the potential for development of new therapeutic approaches involving inhibitors of lipid metabolism that is currently under development in Dr. Kridel’s research in the CGS program. His collaboration with Dr. Lowther in the DDCD program to solve the 3-dimensional structure of FAS in complex with inhibitors such as Orlistat should provide a drug development arm to the group working on lipids and cancer, in which structure-based drug design for FAS inhibitors provides a promising new avenue for development of cancer therapy.
The research on proliferative signaling by ROS, due to its highly interdisciplinary nature, is also ripe for development of collaborative funding, such as a P01 application. The collaboration between Drs. Poole and Daniel will provide new evidence of which proliferative signaling pathways are dependent on ROS, thus opening up the potential for modulating these pathways with antioxidant compounds and other means of regulating the activity of ROS. Once the key target molecules have been identified through the proteomics approach, then the role of modification of these molecules in human cancer can be investigated with members of the Clinical Research Program. In addition, the computational biophysics effort with Dr. Fetrow opens the possibility of structure-based drug design targeted to key signaling proteins modified with cysteine sulfenic acid. Similarly, the collaboration between Drs. Grayson, Poole and Daniel has the potential to open new avenues to modify the generation of immune responses and immunological memory, which could have broad applicability to cancer immunotherapy as well as other areas of immunology.
A major emerging theme in the CGS Program is a focus on tumor microenvironments. Dr. Koumenis’ research on hypoxia in cancers sets the stage for a more general examination of other tumor microenvironments. Dr. Ann Tallant, an established Wake Forest investigator, working on signaling by angiotensin-(1-7) in cancer cells, was recruited to the program as part of this effort. This will also involve new investigators in the CGS Program who are members of the Institute for Regenerative Medicine, working on different types of cell-matrix interactions and cancer stem cells. In addition, new faculty recruiting in the Department of Cancer Biology is targeted to signaling in cancer cell-matrix interactions. The recruitment this year of Dr. Darren Seals, whose expertise is in signaling through podosomes in EMT, is a key element in this effort. This will place the CCCWFU in an excellent position to investigate the problem of heterogeneity in tumors, which is a major hurdle to effective therapy. Progress in this area has the potential to be a substantial scientific contribution from our Cancer Center in future years.
Future research on the genetic cancer resistance trait in mice has obvious extensions to the identification of similar mechanisms in humans. This exciting area of research could provide new insight into the genetic basis of human susceptibility/resistance to cancer, in collaboration with the members of the Cancer Control program and the Genomics Center. This research should dovetail very well with the genetics/genomics research being conducted by Dr. Xu on linkage of genes involved in innate immunity with human prostate cancer. In addition, this research may lead to new therapies for cancer based on activating these innate anticancer immune mechanisms. The recent recruitment of Dr. Purnima Dubey, whose research involves imaging the trafficking of immune cells in intact animals, should markedly enhance research on the immune mechanisms involved. She will also , enhance the immune and imaging capabilities of the group working ononcolytic viruses.
Research on the development of oncolytic viruses is also at a stage that is appropriate for collaborative funding, including the planned resubmission of a P01 application, as well as collaborative R01s to support this research. Future research will involve identifying the molecular basis of sensitivity/resistance to viruses among prostate cancers. This will have broad application to the field of oncolytic viruses, by defining the types of cancers that will be appropriate for oncolytic virus therapy. These studies will involve collaboration with members of the Clinical Research Program, through interactions within the Prostate Center of Excellence, to determine the susceptibility to oncolytic viruses of prostate cancer cells isolated from patients. This research is also being expanded to include brain tumor models developed by Dr. Debinski in the Brain Tumor Center of Excellence. Dr. Debinski’s research on cytotoxins has obvious parallels and overlaps with the induction of cell death by viruses. His experience in translational research will markedly enhance the ability of the group working on oncolytic viruses to move their research towards clinical trials of these promising new anti-tumor agents.
A newly emerging theme that will be developed in the next funding cycle is the transcriptional and epigenetic control of proliferation. Recent recruitments in this area include Dr. Isabelle Berquin, working on the EGFR-stimulating transcription factor YB-1, Dr. Kazushi Inoue, working on the novel tumor suppressor gene, Dmp-1, and Dr. Guangchao Sui, working on YY-1 control of p53. We anticipate that these enthusiastic new faculty will develop into a highly active collaborative group in this important area of signaling related to cancer. This theme has a high degree of potential for translational research in identifying the alterations in gene expression in human cancers, some of which is already underway. For example, Dr. Berquin is collaborating with Dr. Tim Kute (Department of Pathology) to determine the prognostic significance of EGFR and YB-1 coexpression using breast cancer tissue microarrays. Likewise, Dr. Inoue is collaborating with Dr. Greg Kucera and the Tumor Tissue Core to use immunohistochemical staining of human cancer tissues with DMP1-specificantibodies to detect aberrant expression of DMP1 in human cancer. These experiments are currently performed in collaboration with Dr. Greg Hawkins (Center for Human Genomics), Dr. Mark Willingham, and Dr. Tim Kute.