Synthetic Lethal Targeting of Mismatch Repair Defective Cells for Cancer Treatment
Princeton Docket # 15-3159
Researchers in the Department of Molecular Biology at Princeton University have developed a yeast-based high throughput chemical synthetic lethality screen to identify clinically relevant small molecules. Its application has led to the discovery of clinically approved drugs with previously unknown capacity to kill or selectively inhibit the growth of mismatch repair defective cells.
Mismatch repair is a highly conserved DNA repair pathway that plays a key role in maintaining genomic stability and the fidelity of genetic material. Mutations in genes involved in the mismatch repair pathway are implicated in many types of cancer, both hereditary and sporadic. For instance, colorectal cancer is the second leading cause of cancer deaths in the United States, and defects in DNA mismatch repair due to mutations in mismatch repair genes, including MSH2, play a key role towards the development of 20% of hereditary and sporadic colorectal cancers. However, there are no treatment strategies or specifically designed drugs to target cancers with defective or inactivating mutations in mismatch repair pathways.
Loss of mismatch repair also plays a role in the development of chemoresistance, a primary challenge in medical treatments for conditions ranging from cystic fibrosis to cancer. Chemical synthetic lethality is an emerging strategy for specifically targeting cells with cancer-driving mutations. Because mismatch repair deficient tumors accumulate mutations at a high rate and become heterogeneous, targeting the variety of potential pathways altered in these cancer cells is challenging. Therefore, targeting the primary vulnerability is a rational approach for a broad-spectrum treatment.
· Design novel therapeutics to target cancers with mismatch repair defects
· Discover small molecules and pharmaceuticals to target mismatch repair defective cells
· Identify single gene and polygenic resistance targets
· Personalized cancer therapeutics
· Rapid, robust high throughput screen
· Inexpensive approach
· New use for existing drugs
· Selectively inhibit growth and viability of mismatch repair cells while leaving normal cells unharmed
· Larger therapeutic window than traditional chemotherapies
Mismatch repair, high throughput screening, drug design, drug discovery, pharmaceuticals, cancer, chemotherapy, anticancer therapeutics, chemical synthetic lethality, yeast
Alison Gammie, Ph.D., Hahn Kim, Ph.D., and Irene Ojini
Alison Gammie, Senior Lecturer in Molecular Biology and Associate Clinical Member, Cancer Institute of New Jersey, Genome Instability and Tumor Progression
Research in the Gammie lab focuses on DNA mismatch repair, including the regulation of DNA mismatch repair proteins and the mechanism of DNA mismatch repair recognition during replication. Mismatch repair includes identification of a mismatch in the DNA helix, followed by cleavage and excision of the error-containing strand. After the error is removed, a new DNA strand with correct base pairing is synthesized. Because many cancers, particularly those of the colon, are caused by defects in DNA mismatch repair, the Gammie lab seeks to understand oncogenesis in both hereditary and sporadic tumors. Yeast is an optimal experimental organism for studying eukaryotic mismatch repair, as it is amenable to genetic manipulation and has strong homology to the human mismatch repair system. Chromatin immunoprecipitation, tiling microarrays, and high throughput sequencing are other biochemical and molecular tools employed to address questions in DNA mismatch repair.
Dr. Gammie has been a Senior Lecturer at Princeton University since 1998 and was previously a postdoctoral research associate within the Department of Molecular Biology. She is currently the Director of the Program for Diversity and Graduate Recruitment in Molecular and Quantitative Biology, the Director of the Summer Undergraduate Research Program in Molecular and Quantitative Biology, and the NIH Diversity Action Plan Coordinator for the Lewis-Sigler Institute for Integrative Genomics. Additionally, she is the instructor for an inquiry-based laboratory course for graduate students. Dr. Gammie has been recognized for her excellence in mentoring and teaching. In 2013, she was awarded the Princeton University Graduate Mentoring Award and the American Society for Microbiology William A. Hinton Research Training Award. She received her Ph.D. in Molecular Biology from Oregon Health Sciences University and her B.A. in Biology from Reed College.
Hahn Kim, Ph.D., Director, Small Molecule Screening Center, Princeton University
Hahn Kim is the founding director of Princeton University Screening Center (PUSC). He is also a co-founder of Chiromics. As the founding director of PUSC, he conceptualized the initial proposal, planning and build of the screening center. He is currently responsible for all aspects of the strategy and operations of the screening center. His special emphasis on curating a high impact screening collection has led to the identification of exceptionally distinct drug-like chemical probes, providing Princeton University life sciences with an immediate competitive advantage in discovery.
As a co-founder of Chiromics, he was crucial in the inception and development of its proprietary science and technology and currently provides leadership on all of Chiromics’ scientific strategies and platforms. His unique understanding on the generation of novel chemical space and its relevance to biology has inspired the genesis of highly differentiated small molecules, which have contributed significantly in the formation of two biotech companies in addition to the founding of Chiromics. Dr. Kim was a NIH/NCI NRSA postdoctoral fellow with Prof. David MacMillan at Princeton University, where he also received his Ph.D. in organic chemistry.
Intellectual Property Status
Patent applications are pending. Princeton is seeking industrial collaborators for further development and commercialization of this technology.
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