Head and neck squamous cell carcinomas (HNSCCs) are a common human malignancy with 5-year survival rates that have not improved for the past several decades. The incidence of human papilloma virus (HPV)- associated HNSCC is increasing and represents an emerging health problem. Current therapies for HNSCC are associated with considerable toxicities and roughly 50% of patients suffer recurrence. Moreover, advanced stage or recurring HNSCC tumors are frequently chemoresistant. Our long-term goal is to develop novel therapeutic agents and strategies that can be used alone, or in combination with conventional treatments, to improve survival and reduce toxicities in HNSCC patients. Overexpression of anti-apoptotic members of the Bcl-2 protein family, including Bcl-XL and Bcl-2, is observed in a majority of HNSCC and correlates with chemotherapy resistance in this disease. In preliminary studies we have shown that a small molecule inhibitor of Bcl-XL and Bcl-2, ABT-737, synergized with cisplatin to kill HNSCC cells in vitro, via a process involving upregulation of pro-apoptotic Noxa. Additionally, the proteasome inhibitor bortezomib promoted HNSCC cell death in vitro, via induction of pro-apoptotic Bik and Bim, proteins that act as natural antagonists of Bcl-XL/Bcl-2. Bortezomib also induced molecular features of autophagy, and suppression of autophagy enhanced the in vitro resistance of HNSCC cells to bortezomib- induced cell death. The combination of bortezomib and cisplatin exhibited synergism in vitro and enhanced anti-tumor effects against HNSCC xenografts in vivo. HPV-positive HNSCC cells exhibited heighted sensitivity to bortezomib/chemotherapy, and preliminary findings suggest elevated levels of bortezomib-induced autophagy in HPV-positive cells. We hypothesize that HNSCC sensitivity to treatments that incorporate agents targeting the proteasome or anti-apoptotic Bcl-2 family members is modulated by autophagy, HPV, and induction of pro-apoptotic Bcl-2 family members. We propose three Specific Aims.
Specific Aim 1 will investigate cellular mechanisms conferring in vitro sensitivity to proteasome inhibitor-based regimens, by examining the roles of autophagy induction and HPV.
Specific Aim 2 will examine in vitro and in vivo anti- HNSCC effects, and corresponding mechanisms, resulting from targeting of anti-apoptotic Bcl-2 family members with the small molecule inhibitors ABT-737 and GX15-070, alone and in combination with chemotherapy.
Specific Aim 3 will investigate in vivo anti-HNSCC tumor effects and mechanisms resulting from proteasome targeting, alone and in combination with targeting of anti-apoptotic Bcl-2 family members. We anticipate that results from our studies will elucidate unique mechanisms that control the sensitivities of HNSCC cells and tumors to agents targeting the proteasome or anti-apoptotic Bcl-2 family members. We also expect that our results will guide the design of novel treatment strategies and provide the basis for clinical evaluation of synergistic drug combinations in HNSCC.
Head and neck squamous cell carcinomas (HNSCC) are highly resistant to chemotherapy and current therapies cause adverse toxicities. The chemoresistance of these cancers stems from defective cell death pathways. Our studies will investigate novel mechanisms that regulate HNSCC cell death following treatment with agents targeting the proteasome or anti-apoptotic Bcl-2 family members. Additionally, we will examine the in vivo efficacies and mechanisms of these agents against HNSCC tumors when used alone, or in combination, seeking to exploit pathways that confer sensitivity to these agents. Our results will provide the basis for new treatment strategies for this disease.
|Johnson, Daniel E (2015) The ubiquitin-proteasome system: opportunities for therapeutic intervention in solid tumors. Endocr Relat Cancer 22:T1-17|
|Zang, Yan; Kirk, Christopher J; Johnson, Daniel E (2014) Carfilzomib and oprozomib synergize with histone deacetylase inhibitors in head and neck squamous cell carcinoma models of acquired resistance to proteasome inhibitors. Cancer Biol Ther 15:1142-52|
|Dorritie, K A; McCubrey, J A; Johnson, D E (2014) STAT transcription factors in hematopoiesis and leukemogenesis: opportunities for therapeutic intervention. Leukemia 28:248-57|
|Lui, Vivian Wai Yan; Peyser, Noah D; Ng, Patrick Kwok-Shing et al. (2014) Frequent mutation of receptor protein tyrosine phosphatases provides a mechanism for STAT3 hyperactivation in head and neck cancer. Proc Natl Acad Sci U S A 111:1114-9|
|Yazbeck, Victor Y; Li, Changyou; Grandis, Jennifer R et al. (2014) Single-agent obatoclax (GX15-070) potently induces apoptosis and pro-survival autophagy in head and neck squamous cell carcinoma cells. Oral Oncol 50:120-7|
|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|
|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|
|Li, Changyou; Johnson, Daniel E (2013) Liberation of functional p53 by proteasome inhibition in human papilloma virus-positive head and neck squamous cell carcinoma cells promotes apoptosis and cell cycle arrest. Cell Cycle 12:923-34|
|Li, Changyou; Johnson, Daniel E (2012) Bortezomib induces autophagy in head and neck squamous cell carcinoma cells via JNK activation. Cancer Lett 314:102-7|