Pancreatic cancer is the fourth leading cause of cancer mortality in the US, despite significant improvements in diagnostic imaging and operative mortality rates. The 5-year survival rate remains less than 6% because of microscopic or gross metastatic disease at time of diagnosis. Although the treatment of pancreatic cancer remains a challenge, it is entering new era with development of new strategies and trial designs. Because there is an increasing number of novel therapeutic agents and potential combinations available to test in patients with pancreatic cancer and in their PDX models, the identification of robust prognostic and predictive markers for Cancer Stem Cells (CSC) PDX and Circulating Tumor Cells (CTC) PDX and of new targets and relevant pathways is a top priority as well as the design of adequate trials incorporating molecular-driven hypothesis. Here, we examined the efficacy of combined treatments of CEP1430 and CEP1507 in human pancreatic patient-derived xenograft (PDX) cancer cells, and pancreatic PDX CSCs models from the same donors. CEP1430 inhibited the growth of CSCs and CEP1507 inhibited growth of CTCs, while gemcitabine suppressed the viability of non-CSCs [70%] (differentiated tumor Cells). Consistently, in vivo studies showed that CEP1507 when combined with gemcitabine could eliminate the engraftment of human pancreatic cancer CTCs [85%(n=50,p<0.001) and CEP1430 with gemcitabine selectively inhibited [80%] CSCs(n=50,p<0.001), more effectively than the individual agents. These data indicated that administration of CEP1430, which targets CSCs and CEP1507 targets CTCs, may constitute a potential therapeutic strategy for improving the efficacy of gemcitabine to eradicate advanced pancreatic cancer. This study has indicated the potential molecular therapeutic targets to eradicate the tumor – and metastasis-initiating cells (CTCs) and their progenies and development of new effective combination therapies against locally advanced and metastatic pancreatic cancer. Using PDX models, we confirmed the effectiveness and selectivity of the identified treatment responses with TGI at 97% with CEP1430.
Note: This abstract was not presented at the meeting.
Citation Format: Michael Sharma, Maulik Jain, Cristian Sharma, Karina Amezcua, Natalee Amezcua, Reed Hasson, Miriam Navel, Donna Stanton, Satya Narayan, Karl Kramberger, Rubio Punzalan, Jitesh Jani, Douglas Foster, Jay P. Sharma. Novel drug candidates cep1430 and cep1507 for targeting pancreatic patient-derived xenograft cancer stem cell and circulating tumor cell models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3889. doi:10.1158/1538-7445.AM2017-3889