In the past decade, while the overall cancer incidence rate tends to declining, pancreatic cancer remains the most aggressive human cancer with a very poor survival rate (3-6% for 5-year survival) and no improvement in outcomes. For example, in the United States, the estimated new cases of pancreatic cancer and deaths from this disease have grown over the past six years (2008: 37,680 new cases and 34,290 deaths;2013: 45,220 new cases and 38,460 deaths). The challenge of this disease is basically due to the striking inherent resistance of pancreatic cancer to treatment (chemotherapy, radiation). The goal of this R21 exploratory project is to explore the mechanistic novelty and anti-pancreatic cancer efficacy of a novel anticancer agent (designated FL118) that is designed to overcome a common mechanism of treatment resistance resulting from the increased expression of one or more antiapoptotic proteins (survivin, Mcl-1, XIAP, cIAP2) from the inhibitor of apoptosis (IAP) and Bcl-2 families. The other major mechanism of treatment resistance of pancreatic cancer is the loss of functional p53 (mutated or null). In this regard, FL118 selectively inhibits the expression of survivin, XIAP, cIAP2 and Mcl-1 in a p53 status (wild type, mutant or null) independent manner. Consistently, we have reported that many non-pancreatic cancers are sensitive to FL118, independently of their p53 status. We hypothesize that although FL118 has structural similarity to camptothecin, FL118 is a novel anticancer agent with mechanisms of action distinct from other camptothecin analogs such as topotecan, and FL118 is superior for treatment of pancreatic cancer when compared to current FDA approved camptothecin analogs (e.g. topotecan) or other anticancer agents (gemcitabine). The hypothesis will be tested in three Specific Aims:
Aim 1 : Characterize FL118 target selectivity using topotecan as a comparative control. We will use multiple approaches to determine FL118 target selectivity. This includes FL118 and topotecan in response to treatment resistant factors of Top1 mutations;expression of survivin, Mcl-1, XIAP and/or cIAP2;p53 mutant or p53 null;expression of ABCG2/BCRP or ABCC4/MRP4;and induction of apoptosis.
Aim 2 : Determine FL118 efficacy in mouse models of treatment resistant human pancreatic cancer cell-established xenografts. We will use both topotecan and gemcitabine (the most commonly used single regimen drug for pancreatic cancer treatment in clinical practice) for efficacy comparative studies.
Aim 3 : Determine FL118 efficacy against xenografts directly derived from pancreatic cancer patients. Both topotecan and gemcitabine will also be used as comparative controls for efficacy studies in this system. Same as in Aim 2 above, both subcutaneous and orthotopic xenograft tumor models will be used in these studies. We expect that this project would not only provide new hopes and perspectives for effective management of pancreatic cancer, but may also open new research strategies or directions to conquer this deadly disease.
The five-year survival rate for pancreatic cancer is only 3-6%. About 45,220 new cases occur and 38,460 peoples will lose their battle with this disease in 2013 only in the United States. This is largely due to the disease being resistant to FDA approved treatments. Therefore, overcoming resistance to treatment is a major goal and challenge in the field. This proposal will develop a novel drug platform that will overcome pancreatic cancers of treatment resistance and thus, prolong and save lives of pancreatic cancer patients.
|Westover, David; Ling, Xiang; Lam, Hong et al. (2015) FL118, a novel camptothecin derivative, is insensitive to ABCG2 expression and shows improved efficacy in comparison with irinotecan in colon and lung cancer models with ABCG2-induced resistance. Mol Cancer 14:92|
|Westover, David; Li, Fengzhi (2015) New trends for overcoming ABCG2/BCRP-mediated resistance to cancer therapies. J Exp Clin Cancer Res 34:159|
|Ling, Xiang; Xu, Chao; Fan, Chuandong et al. (2014) FL118 induces p53-dependent senescence in colorectal cancer cells by promoting degradation of MdmX. Cancer Res 74:7487-97|