# A novel small molecule targeting protein translation for pancreatic cancer treatment

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2022 · $186,416

## Abstract

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.

## Key facts

- **NIH application ID:** 10508642
- **Project number:** 1R21CA273506-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** RUIWU LIU
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $186,416
- **Award type:** 1
- **Project period:** 2022-07-04 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10508642

## Citation

> US National Institutes of Health, RePORTER application 10508642, A novel small molecule targeting protein translation for pancreatic cancer treatment (1R21CA273506-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10508642. Licensed CC0.

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