Improving the potency of novel PRMT5 inhibitor with nanocrystal technology to treat pancreatic cancer - Project Summary Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignant neoplasia with an extremely low 5-year overall survival (OS) rate (~10%). Its current standard first-line treatment is the combination of Gemcitabine/nano albumin-bound-Paclitaxel (Gem/NabP), but with a median OS of only ~8.5 months and considerable toxicity. The poor therapeutic outcomes underscore the urgent need for innovative PDAC treatment strategies. Gem/NabP have been reported to activate the nuclear factor (NF)-κB and drive their therapeutic resistance in PDAC. Moreover, aberrant expression of NF-κB is a pivotal driver of PDAC. We were the first to discover that PRMT5 methylates NF-κB to activate genes crucial to PDAC progression. Moreover, Kaplan-Meier plots show that PDAC patients with high PRMT5 expression have dramatically worse OS than those with low PRMT5 expression. Thus, effective NF-κB inhibitors and their combination with Gem/NabP are expected to enhance PDAC treatment. Recently, the protein arginine methyltransferase 5 (PRMT5) was identified as a synthetic lethality combinatorial target with Gem in PDAC via CRISPR screening, further supporting the promise of PRMT5 inhibitor and Gem/NabP combination. To target PRMT5 in PDAC, our lab has identified a potent small molecule inhibitor of PRMT5, PR5-LL-CM01 (abbreviated CM01) (US Patent No. 11,034,689). We showed that CM01 exerts an anti-cancer effect in PDAC in vitro and in vivo. Preliminary data also revealed no overt systemic toxicity in mice. Importantly, CM01 was more potent than GSKi and JNJi in killing PDAC cells, avoiding the concern of myelosuppression toxicity of GSKi and JNJi. CM01 possesses the patented unique chemical structure, and thus, is a highly promising PRMT5 inhibitor warranted for further development. Despite the therapeutic potential, CM01 has low water solubility, which significantly compromises its bioavailability. In this proposal, we aim to improve the efficacy of CM01 by formulating it with our patented albumin-coated nanocrystal (NC) (or Abxtal) technology, which does not require solvents or chemical surfactants for solubilizing hydrophobic CM01. In a pilot experiment, we produced Abxtal-CM01 of <100nm (~87nm). In this study, we hypothesize that nanocrystal Abxtal-CM01 will maintain biological functions of CM01, improve its tumor delivery and PDAC inhibition efficacy, and show synergy with Gem/NabP in PDAC treatment in vivo. To test this central hypothesis, we propose to pursue the following aims: Aim 1. Scale-up production and characterization of NC form of the PRMT5 novel inhibitor, Abxtal-CM01. Aim 2. Determine the biological functions of Abxtal-CM01 in vitro and its antitumor efficacy alone or in combination with Gem/NabP in PDAC model in vivo. IMPACT: Upon successful completion, this research will have established that NC formulation of PRMT5 inhibitor Abxtal-CM01 can provide an effective treatment of PDAC, a disease in urgent need of effective treatments.
