Osteosarcoma is the most common primary bone cancer, and the third most common solid tumor in adolescents, affecting nearly 1000 people per year in the United States. This disease desperately needs new therapies, since nearly 40% of those diagnosed will die of their disease, and the survival for this disease has not truly improved in more than 25 years. Signals from the ERBB family of receptor tyrosine kinases contribute essential signals to osteosarcoma, and that a pan-ERBB inhibitor is more effective at stopping the growth of osteosarcoma than is a selective EGFR inhibitor or an inhibitor that blocks signals from either EGFR or Her-2. Most osteosarcoma is do express EGFR, and that those which express Her-2 have a greater propensity to metastasize. However, the specific contributions of Her-2 and Her-4 to malignant behavior in osteosarcoma are largely undocumented. Of the four ERBB family members, Her-4 is the least well characterized. Based upon the in vitro superiority of pan ERBB inhibition compared to inhibition of EGFR and Her-2 alone, it is hypothesized that Her-4 makes unique contributions to osteosarcoma pathology. Likewise, since Her-2 is associated with a more metastatic phenotype, it is likely that it also has unique contributions. This proposal is intended to evaluate the scientific basis for therapies targeting the ERBB family of receptor tyrosine kinases for treating osteosarcoma, by defining the unique contributions of each of the family members within this disease. In the first specific aim, molecular approaches are used to evaluate the precise contributions of each ERBB family member to osteosarcoma biology, focusing particularly on the role of Her-4 in the nucleus and its potential to regulate the expression of other genes. In the second specific aim, a large bank of archival osteosarcoma specimens is evaluated for expression of members of the ERBB family, correlating expression with clinical outcome. In the third specific aim, to novel orthodontic osteosarcoma xenograft models are used to evaluate the therapeutic potential of a specific pan ERBB inhibitor, PF00299804. The effect of eliminating individual ERBB family members also is evaluated. When successfully completed, the proposed studies will define the specific contributions of each ERBB family member to osteosarcoma biology, understanding their role in a clinical context, and potentially providing the basis for using a pan ERBB inhibitor for treating patients with osteosarcoma. Should the underlying hypothesis be proven, these studies would pave the way for new clinical trials for children who desperately need new treatments.
The development of molecularly targeted small molecule medicines has brought nearly miraculous improvements in the outcome of many of the most deadly cancers, but this miracle has largely left rare cancers and pediatric diseases behind, in part because there has not been enough effort devoted to evaluating the biologic basis and therapeutic opportunities for using these drugs in pediatric cancers such as osteosarcoma. This project will evaluate in the laboratory setting the possibility of using a specific category of molecular medicines, pan-ERBB inhibitors, for osteosarcoma, a bone cancer that strikes adolescents and young adults, causing disability in all patients and death in about 40% of those diagnosed. With the studies proposed, we will define the role that the ERBB family plays in promoting osteosarcoma, determining whether or not the pan-ERBB inhibitors being developed for lung and breast cancer might also bring hope to young people afflicted with bone cancer.
|Woodfield, Sarah E; Guo, Rong Jun; Liu, Yin et al. (2016) Neuroblastoma patient outcomes, tumor differentiation, and ERK activation are correlated with expression levels of the ubiquitin ligase UBE4B. Genes Cancer 7:13-26|
|Hughes, Dennis P M; Kummar, Shivaani; Lazar, Alexander J (2015) New, tolerable ?-secretase inhibitor takes desmoid down a notch. Clin Cancer Res 21:7-9|
|Rivera-Valentin, Rocio K; Zhu, Limin; Hughes, Dennis P M (2015) Bone Sarcomas in Pediatrics: Progress in Our Understanding of Tumor Biology and Implications for Therapy. Paediatr Drugs 17:257-71|
|Zhu, Shiguo; Denman, Cecele J; Cobanoglu, Zehra S et al. (2015) The narrow-spectrum HDAC inhibitor entinostat enhances NKG2D expression without NK cell toxicity, leading to enhanced recognition of cancer cells. Pharm Res 32:779-92|
|Zhang, Fuwu; Zhang, Shiyi; Pollack, Stephanie F et al. (2015) Improving paclitaxel delivery: in vitro and in vivo characterization of PEGylated polyphosphoester-based nanocarriers. J Am Chem Soc 137:2056-66|
|Zage, Peter E; Sirisaengtaksin, Natalie; Liu, Yin et al. (2013) UBE4B levels are correlated with clinical outcomes in neuroblastoma patients and with altered neuroblastoma cell proliferation and sensitivity to epidermal growth factor receptor inhibitors. Cancer 119:915-23|
|Irwin, Mary E; Nelson, Laura D; Santiago-O'Farrill, Janice M et al. (2013) Small molecule ErbB inhibitors decrease proliferative signaling and promote apoptosis in philadelphia chromosome-positive acute lymphoblastic leukemia. PLoS One 8:e70608|
|Nelson, Laura D; Bender, Christian; Mannsperger, Heiko et al. (2012) Triplex DNA-binding proteins are associated with clinical outcomes revealed by proteomic measurements in patients with colorectal cancer. Mol Cancer 11:38|
|Hua, Yingqi; Gorshkov, Kirill; Yang, Yanwen et al. (2012) Slow down to stay alive: HER4 protects against cellular stress and confers chemoresistance in neuroblastoma. Cancer 118:5140-54|
|Hu, Jiemiao; Liu, Xinli; Hughes, Dennis et al. (2011) Herceptin conjugates linked by EDC boost direct tumor cell death via programmed tumor cell necrosis. PLoS One 6:e23270|