Cancer Biology and Therapeutics Program Activities and Selected Scientific Reports
The 37 members of Cancer Biology & Therapeutics (CBT) Program come from 12 academic Departments at The Geisel School of Medicine and Dartmouth College. They are organized around three translational cancer research themes for the purpose of emphasizing the elucidation of pathways that present opportunities as well as challenges in cancer diagnosis, classification, prevention, and treatment:
- Cancer cell signaling and metabolism
- Cell cycle and genome stability
- Chromatin biology and oncogenic transcription
The CBT Program has regular monthly meetings, an annual retreat and other activities during each academic year.
CBT contributes to the academic dialogue at Dartmouth through active dissemination of scientific and clinical findings, as well as recruiting leaders in the field to Dartmouth for presentations. Members contribute frequently to an array of Dartmouth seminar series, including the Cancer Center Grand Rounds, Genomic Medicine Grand Rounds, Biochemistry & Cell Biology and Molecular & Systems Biology seminars, as well as Chemistry colloquia.
In the clinical arena, members of Cancer Biology and Therapeutics are embedded in Cancer Center Clinical Oncology Groups/Tumor Boards at Dartmouth-Hitchcock Medical Center, location in Lebanon, NH. Todd Miller, PhD, is the Scientific Director of the Comprehensive Breast Program and Breast Tumor Board; Frederick Lansigan is the Medical Director of Inpatient Hematology/Oncology Services; Lionel D. Lewis and Konstantin Dragnev co-direct the Early-Phase Trial Program (EPTP), for which Alan Eastman PhD, Yolanda Sanchez, PhD, Jack Hoopes DVM, PhD (TEC), Mary Jo Turk (ICI) and Brock Christensen (CPS), are members of the executive committee.
Regionally, Cancer Biology and Therapeutics co-organizes and co-sponsors the yearly Regional Symposium on Genome Stability and Cancer in collaboration with the University of Vermont, University of Massachusetts Medical Center, Jackson Laboratories and Worcester Polytechnic. The regional clinical trials network New England Oncology Network (NEON) provides additional opportunities for collaboration.
Junior faculty mentorship is essential for maintaining the CBT Program’s current and future successes. In collaboration with Dartmouth’s NIH-funded SYNERGY Clinical and Translational Science Institute, senior CBT members provide formal mentorship for Program junior faculty for securing extramural funding and for the design of clinical trials. CBT members Arminja Kettenbach PhD, Bing He PhD and Michael J. Ragusa, PhD were recently awarded MIRA funding and four recent CBT recruits Diwakar R. Pattabiraman, PhD, Xiaofeng Wang, PhD, Christopher J Shoemaker, PhD, and Aaron McKenna, PhD, are K99/R00 awardees. Our faculty are heavily involved in the training of fellows, residents and medical students, as well as classroom instruction for medical, graduate and undergraduate students across the Dartmouth campus and Dartmouth-Hitchcock Medical Center.
Novel small molecules to target tumors with dysregulated Ras signaling due to NF1 loss or KRAS mutations
A team of CBT investigators—Sanchez, Lewis, Hoopes (TEC), Pogue (TEC), Tomlinson, and Ratner (Univ. of Cincinnati), Gerber, Wu, Greene (now at Univ. of PA) Dragnev, Smith, and Barth (TEC)—seek to identify and develop compounds and experimental drugs with selective efficacy against cancer cells with dysregulation of Ras signaling by loss of NF1 or mutation of KRAS, which are common oncogenic alterations that lack targeted therapies. With of the arrival of Dr. Leach to CBT, new opportunities in fish, mouse and organoid models of mutant Ras-driven cancers have enhanced this focus area within the CBT program.
Wnt signaling in cancer
CBT members Ahmed, Cole and Cheng (now at Baylor College of Medicine) study the role of the Wnt pathway in cancer development. Pathways such as the Wnt pathway that are required for accurate development and tissue specification are often dysregulated in cancer, linking studies of animal development and cancer biology at a fundamental level. Because the core Wnt signaling components are conserved across animal species, use of genetically tractable model systems, such as fruit flies, has revealed most of what we know today about this pathway. In CBT, Dr. Ahmed uses a combination of genetic and cell biological approaches to study Wnt signaling in Drosophila melanogaster from studies initially supported by early NCCC Prouty Pilot funding. Inactivation of the tumor suppressor Adenomatous polyposis coli (APC) triggers the development of the vast majority of colorectal carcinomas.
Phosphorylation signaling in cell division
The goal of cell division is the equal, error-free distribution of duplicate chromosomes into each daughter cell. Errors in cell division result in aneuploidy, which is common in almost all cancers. Protein phosphorylation is a regulatory mechanism that facilitates accurate chromosome segregation during mitosis and is orchestrated by a host of cell cycle kinases and phosphatases. CBT features a highly collaborative group of investigators (Kettenbach, Gerber, Miller Moseley, Griffin, Cole and Compton) that study the mechanisms that underlie mitotic entry, progression and exit, with the long-term goal of identifying new entry points for therapeutic intervention. This group uses a combination of cancer genetics, biochemistry, proteomics, imaging and model organisms to achieve their research goals.
Chromosome instability and cancer
Numerical chromosome instability (CIN) results in aneuploid progeny during cell division. Some cancer cells are stably aneuploid, while others frequently gain and lose chromosomes. CIN generates tumor heterogeneity, which contributes to drug resistance and poor patient outcomes. The Compton laboratory studies the cellular and molecular mechanisms that dictate chromosome movements during cell division. These chromosome movements are required to properly position chromosomes for separation and are defined by microtubule-chromatid attachments. Early in mitosis, there are many erroneous attachments that are formed transiently and corrected by high rates of microtubule turnover. Later in mitosis, these microtubule attachments become more stable as chromosomes become accurately oriented. The long-term goal of this research is to identify new entry points for therapeutic intervention that leverage chromosome instability and aneuploidy and associated signaling pathways to selectively target cancer cells.
Overcoming anti-estrogen resistance in ER+ breast cancer
New Hampshire has the highest incidence of breast cancer in the US, and breast cancer is the most commonly diagnosed cancer in New Hampshire and Vermont. In addition, approximately 2/3 of breast cancers are estrogen receptor α-positive (ER+). Roughly 1/3 of ER+ breast cancers will develop resistance to adjuvant anti-estrogen therapy, and advanced disease ultimately becomes resistant to all available agents and is almost uniformly fatal. Dr. Miller’s group is focused on developing novel therapeutic strategies to prevent and abrogate anti-estrogen resistance. A research team assembled by Dr. Miller that includes Drs. Lewis, Eastman, Demidenko (CPS), Schwartz, Barth (TEC), Kettenbach, Marotti and collaborators at Genentech have led studies investigating the optimal scheduling of drugs during therapy.