Pancreatic cancer (PC) is the fourth leading cause of cancer deaths in the US with a mean survival time of less than 6 months and an overall 5-year survival rate of less than 5 percent. Recently a distinct population of cancer cells with 'stem cel', 'initiating', or 'progenitor'properties has been identified and characterized to play a significan and critical role in tumor development, maintenance, tumor metastases and therapy resistance, factors known to promote the high lethality of PC. My long term goal is to identify therapeutic strategies that target pancreatic cancer 'stem cells'(PCSCs). The atypical protein kinase C (aPKC) isozyme, PKC?, is over- expressed in a subset of human pancreatic tumors and plays a critical role in the transformed growth of PC cells in vitro, and in their tumorigenesis and metastasis in vivo. Here, we generated Panc-1 PCSCs in "low adherent" 3D culture. The 'stem cell-ness'of this population was functionally characterized by the ability of these cells to clonaly expand, migrate toward the chemokine, SDF-1, enhanced ability to grow in soft agar, and increased expression of SC markers. Preliminary data suggests a role for PKC? in PCSCs. Furthermore, PCSC growth can be inhibited with a molecularly targeted inhibitor of PKC?, aurothiomalate (ATM).
The specific aims of this project are to 1) elucidate the role of PKC? in PCSC transformed growth, tumorigenesis, and tumor metastasis;and 2) evaluate the ability to inhibit the PCSC phenotype with ATM alone and in combination with conventional chemotherapeutics.
These aims will be carried out using proliferation, survival, and stem cell marker expression assays along with subcutaneous and orthotopic tumor models.
Since ATM is an FDA-approved drug, and already in clinical trials for the treatment of lung and ovarian cancer, the proposed studies have the potential to rapidly impact the therapy of pancreatic cancer patients, who currently have few effective options for treatment.
|Butler, Amanda M; Scotti Buzhardt, Michele L; Erdogan, Eda et al. (2015) A small molecule inhibitor of atypical protein kinase C signaling inhibits pancreatic cancer cell transformed growth and invasion. Oncotarget 6:15297-310|
|Butler, Amanda M; Scotti Buzhardt, Michele L; Li, Shuhua et al. (2013) Protein kinase C zeta regulates human pancreatic cancer cell transformed growth and invasion through a STAT3-dependent mechanism. PLoS One 8:e72061|