Friday, May 9, 2025
5/9/2025
A novel small molecule targeting protein translation for pancreatic cancer treatment - Summary Pancreatic cancer, a leading cause of cancer mortality in the US with a five-year survival of around 10%, is one of the most lethal cancers. Surgery, which offers the only realistic hope, has a limited role, with only about 20% of patients undergoing resection of any variety. Current chemotherapy or radiation therapy regimens offer minimal or no help. Thus, there is a dire need for new agents against pancreatic cancer. Recently, we designed and synthesized multiple promising small molecule inhibitors with strong in vivo anticancer efficacy. Our novel lead agent LLS132 shows high potency in reducing pancreatic cancer cell growth and significantly reducing in vivo growth of these tumors. In preliminary studies, LLS132 (30 mg/kg; i.p 5x/week) reduced pancreatic tumor growth by 78%, compared to controls, and this effect was superior to that of gemcitabine (100 mg/kg; i.p 2x/week), which reduced tumor growth by only 48%. Of note, LLS132 was safe with mice showing no liver toxicity or changes in body weight. In addition, using a RNA-seq analysis of human pancreatic cancer Panc-1 cells treated with LLS132, we identified ribosomal biogenesis as a key biological process affected by LLS132. Furthermore, LLS132 synergized with nab-paclitaxel in both Panc-1 and MIA PaCa-2 pancreatic cancer cell lines. These preliminary results strongly indicate that LLS132 is safe and effective in multiple preclinical models of PDA, and provides synergistic therapeutic effects with nab-paclitaxel therapy, warranting further evaluation. The objective of this R21 project is to develop an effective new drug combination for PDA. Particular emphasis will be given to the involvement of ribosomal biogenesis as the primary biological process affected by LLS132. Our hypothesis is that the LLS132/nab-paclitaxel drug combination will show synergistic effect in vivo against PDA. In Aim 1, we propose to evaluate the safety, pharmacokinetics and pharmacodynamics of LLS132 alone and in combination with nab-paclitaxel, whereas in aim 2, we propose to determine the efficacy and key molecular drivers of the LLS132/nab-paclitaxel drug combination in preclinical models of PDA. To achieve these goals, we will use multiple distinct, yet complementary, clinically relevant preclinical models of PDA. These include organoid-grafted organoids (OGOs) and a transgenic PDA mouse model (LSL-KrasG12D, LSL- Trp53R172H/+, Pdx1-Cre; KPC). At the completion of these studies, we expect to have determined key pharmacological parameters of this promising novel drug combination for PDA treatment, and setting the stage for further research on human subjects. Given the importance of PDA and the lack of effective agents against it, we believe that the proposed work holds the promise of a significant advance in this area.
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