Our objective is to identify genetic modulators of risk, prognosis and response to therapy for squamous cell carcinoma of the head and neck (SCCHN). We will employ two basic study designs to achieve three aims: a case control study to identify single nucleotide polymorphisms (SNPs) associated with SCCHN risk (Aim 1), and a patient cohort study to identify SNPs associated with progression free survival (PFS)(Aim 2) and treatment response (Aim 3), with a focus on platinum-based therapy. Our large specimen collection with over 1000 controls and 750 SCCHN cases to date with detailed clinical, pathologic and survival data for cases and demographic and risk factor data for all subjects provides us the unique ability to carry out these studies. DNA repair pathway genes have been implicated in both SCCHN risk and response to therapy. Preliminary data from our current SPORE study are consistent with other recent reports that show reduced DNA repair capacity, mediated by nucelotide excision repair (NER), may be associated with PFS in platinum-treated cases. We have recently expanded our genotyping analysis to a comprehensive 384 single nucleotide polymorphism (SNP) panel that includes all of the gene members of the NER pathway. In a preliminary haplotype association analysis, we have identified several gene haplotypes associated with either enhanced or reduced PFS in platinum-treated cases. Complementary to this hypothesis-driven candidate gene approach, genome wide association studies (GWAS) can identify new susceptibility genes without making a priori biological assumptions. We plan to design a 1536 SNP panel by implementing a hybrid strategy for SNP selection incorporating both candidate DNA repair pathway and cell cycle genes and a noncandidate gene approach based on emerging data from ongoing phase I GWAS studies. This integrated approach applied toward the selection of genetic variants in a large sample size provides the opportunity to identify and characterize novel genetic biomarkers of susceptibility, prognosis and prediction of therapeutic response. We will use SNP- and haplotype-based approaches in our evaluation of the role of genetic factors and their interactions with the environment in SCCHN risk and disease outcome.
SCCHN is a leading cause of cancer death worldwide and therefore, there is a need for a systematic approach to further evaluate complex pathways in SCCHN risk, prognosis and prediction of treatment response. The identification of subgroups at high-risk for developing SCCHN and poorer clinical prognosis has implications for future chemoprevention intervention strategies and for treatment decisions, respectively.
|Pollock, Netanya I; Grandis, Jennifer R (2015) HER2 as a therapeutic target in head and neck squamous cell carcinoma. Clin Cancer Res 21:526-33|
|Li, Jing; Jie, Hyun-Bae; Lei, Yu et al. (2015) PD-1/SHP-2 inhibits Tc1/Th1 phenotypic responses and the activation of T cells in the tumor microenvironment. Cancer Res 75:508-18|
|Johnson, Daniel E (2015) The ubiquitin-proteasome system: opportunities for therapeutic intervention in solid tumors. Endocr Relat Cancer 22:T1-17|
|Sen, Malabika; Paul, Kathleen; Freilino, Maria L et al. (2014) Systemic administration of a cyclic signal transducer and activator of transcription 3 (STAT3) decoy oligonucleotide inhibits tumor growth without inducing toxicological effects. Mol Med 20:46-56|
|Parikh, Rahul A; Appleman, Leonard J; Bauman, Julie E et al. (2014) Upregulation of the ATR-CHEK1 pathway in oral squamous cell carcinomas. Genes Chromosomes Cancer 53:25-37|
|Johnston, Paul A; Sen, Malabika; Hua, Yun et al. (2014) High-content pSTAT3/1 imaging assays to screen for selective inhibitors of STAT3 pathway activation in head and neck cancer cell lines. Assay Drug Dev Technol 12:55-79|
|Qian, Wei; Wang, Jingnan; Roginskaya, Vera et al. (2014) Novel combination of mitochondrial division inhibitor 1 (mdivi-1) and platinum agents produces synergistic pro-apoptotic effect in drug resistant tumor cells. Oncotarget 5:4180-94|
|Klein, Jonah D; Sano, Daisuke; Sen, Malabika et al. (2014) STAT3 oligonucleotide inhibits tumor angiogenesis in preclinical models of squamous cell carcinoma. PLoS One 9:e81819|
|Peyser, Noah D; Grandis, Jennifer R (2014) Genetic mutations in head and neck cancer: utilizing existing treatments. Pharmacogenomics 15:1553-5|
|Li, Changyou; Egloff, Ann Marie; Sen, Malabika et al. (2014) Caspase-8 mutations in head and neck cancer confer resistance to death receptor-mediated apoptosis and enhance migration, invasion, and tumor growth. Mol Oncol 8:1220-30|
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