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Targeting Co-dependent Molecular Pathways in Oral Cancer

Integrative Biology and Infectious Diseases Branch
Division of Extramural Research 

The primary goal of this initiative is to identify co-dependent survival and proliferation pathways in oral cancer cells that would in turn facilitate the development of new targeted and effective therapies. The recently identified genomic abnormalities in human oral cancer samples will be leveraged to elucidate potential signaling pathways that can be targeted with combination therapy approaches. This initiative would emphasize collaboration of multi-disciplinary research teams to identify oral cancer specific therapeutic targets using novel chemical entities and exploitation of screening strategies, such as RNA interference and synthetic lethality approaches. The use of validated cell lines, novel 3D cultures, and other clinically-relevant model systems will be encouraged.

Oral Squamous Cell Carcinomas (OSCC) represent the majority of Head and Neck Cancers with ~45,000 new cases diagnosed each year in the U.S. In comparison with other cancer types, the 5-year survival rate of OSCC patients is ~50% and has improved only marginally during the past few decades. Impact of current cytotoxic therapies for oral cancer is limited by disease recurrence and resistance to therapy. In addition to the limited survival, some of the major problems with the current treatment modalities of oral cancers include their lack of specificity and the attendant cytotoxicity to normal cells that lessen their therapeutic effectiveness. Furthermore, current treatment regimens that include surgery, radiation, and chemotherapy often lead to morbidity that reduces the quality of life for patients.
Gaps and Opportunities:
Advances in genomics, bioinformatics analyses, and high throughput screening methods have provided us with the tools to identify and better understand abnormalities of signaling pathways in cancer cells. While progress has been made in the preliminary genomic, epigenomic and transcriptomic characterization of human oral cancers, considerable knowledge gaps remain in areas such as: elucidation of oral cancer specific signaling pathways, integration and exploitation of -omic analyses towards mechanism-based therapies, and systematic validation of potential cancer specific signaling pathways that are “druggable”.

Recent data indicate that cancer cells become dependent on distinct molecular pathways that involve growth factor signaling, DNA repair and cellular metabolism and such pathways provide potential avenues for therapeutic targeting. Targeted and rational therapies based on distinct signaling abnormalities of cancer cells have the potential to supersede current therapies with their dose limiting toxicities. The dependency of cancer cells on various specific cellular signaling mechanisms has been described as oncogene addiction, synthetic lethality, genetic dependency and tumor suppressor hypersensitivity depending on the context. Some examples of the above mentioned phenomena include: (i) hypersensitivity of BRCA1 mutant breast cancer cells to inhibitors of the DNA repair protein PARP1; (ii) sensitivity of p53 deficient cells to Check point kinase 1 (CHK1) inhibition; and (iii) synthetic lethality of cancer cells exposed to Metformin and glucose withdrawal. More importantly, recent mathematical modeling studies based on outcome data from cancer clinical trials also suggest that targeted simultaneous combination therapy is superior to mono-therapy or sequential therapy. This initiative will support multidisciplinary team studies aimed at identifying signaling pathways using clinically relevant model systems that would inform therapeutic strategies based on the genomic complexity and heterogeneity of OSCC.

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This page last updated: February 26, 2014