Kwok Yin Tsang

Effect of molecular weight of PGG-paclitaxel conjugates on in vitro and in vivo efficacy.

Polymeric prodrugs are one of the most promising chemotherapeutic agent delivery approaches, displaying unique drug release profiles, serum stability, formulation flexibility, and reduced drug resistance. One of the most important aspects of a polymeric prodrug, albeit a less-extensively studied one, is the polymers molecular weight, which affects particle formation, drug release and PK/PD profiles, drug stability, and cell uptake; these factors in turn affect the prodrugs maximum tolerated dose and anticancer efficacy. Poly(L-γ-glutamylglutamine) (PGG) is a linear polymer designed to improve the therapeutic index of attached drugs. In this study we selected poly(L-γ-glutamylglutamine)-paclitaxel (PGG–PTX), as a model system for the methodical investigation into the effects of the poly(L-γ-glutamylglutamine) backbone molecular weight on its pharmacological performance. The polymeric prodrug was characterized by NMR, DLS and GPC-MALS, and its anticancer activity in vitro and in vivo was assessed. Herein we present data which provide valuable insight into improving anticancer polymer-based prodrug design and development.

Abstract 5918: A novel glutathione S-transferase P (GSTP) siRNA (NDT-05-1040) for the treatment of KRAS-driven non-small cell lung cancer

Lung cancer is the most common form of cancer worldwide and the leading cause of cancer-related deaths. Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancers, and KRAS mutation occurs in 25-30% of NSCLC. However, to date, direct therapeutic targeting of KRAS has not been achieved. Our approach to developing a KRAS mutant NSCLC therapeutic agent was to identify a selective novel target involved in modulating signaling proteins in the RAS pathway without impacting healthy cells. Numerous studies have shown that glutathione S-transferase P (GSTP) is strongly upregulated in many cancer types, specifically lung, colon, and pancreas. Besides being a well-known Phase II detoxification enzyme, GSTP is also known to influence cell signaling through interaction with MAP kinases such as JNK and c-jun. We therefore hypothesized that GSTP knockdown (KD) could be an effective therapeutic approach to treat KRAS mutant tumors. To test this hypothesis, we designed a series of novel GSTP siRNAs and identified our lead candidate, a highly potent and selective GSTP siRNA (NDT-05-1040) to specifically target and downregulate GSTP protein. A panel of KRAS mutant NSCLC cell lines was utilized to determine the GSTP KD potency and antiproliferative activity of NDT-05-1040. Western blot analysis and co-immunoprecipitation (co-IP) were conducted to identify the proteins that were regulated by GSTP in the proliferation and apoptosis pathways. These studies demonstrated that NDT-05-1040 is a very potent and selective GSTP siRNA. Furthermore, transfection of NDT-05-1040 led to significant growth inhibition and induced apoptosis in NSCLC cells without affecting normal cell viability. Western blot analysis showed that NDT-05-1040 effectively decreased the phosphorylation of CRAF, ERK, MEK, in the MAP kinase pathway. Interestingly, with NDT-05-1040 treatment, the phosphorylation of Akt and mTOR in the PI3K pathway was also decreased. Moreover, the activity of p-JNK, PUMA, caspase-3/7, and p53 in the KRAS mutant cells was upregulated by NDT-05-1040. Co-IP experiments demonstrated that GSTP formed a complex with both p-CRAF and JNK. In summary, GSTP KD by NDT-05-1040 targeted the RAS/MEK/ERK, Akt, mTOR and apoptosis pathways. This selective multipronged attack on the growth and survival pathways of cancer cells makes it a compelling target and could potentially serve as a novel therapeutic agent for KRAS mutant NSCLC. Citation Format: Cima Cina, Jens Harborth, Zhihong O9Brien, Nish Beltran-Raygoza, Jung-kang Jin, Jessica Xu, Sang Jun Lee, Kwok Tsang, Jiping Yao, Roger Adami, Sonya Zabludoff, Wenbin Ying. A novel glutathione S-transferase P (GSTP) siRNA (NDT-05-1040) for the treatment of KRAS-driven non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5918.

Abstract 4578: A novel polymer-anticancer drug micelle formulation showing enhanced efficacy over Abraxane

Advances in the development of novel nanocarriers and their applications in the area of drug delivery have inspired and created new opportunities for anticancer formulation development. About 10 anticancer nanomedicines in various dosage forms of liposomes and polymeric micelles have been approved since 1995, with albumin-bound paclitaxel (Abraxane) being a milestone in the treatment of a variety of aggressive cancers. These nanomedicines outperform the low molecular weight anticancer chemotherapeutic agents by their favorable pharmacokinetics and tissue distribution, resulting in improved efficacy and concomitantly decreased systematic side effect. We have developed a novel linear water soluble polymeric nano-carrier, poly-(L-γ-glutamylglutamine) (PGGA) by addition of a hydrophilic glutamic acid layer onto a poly-(L-glutamic acid) backbone. PGGA is proved to be versatile as nanocarrier for making both polymer drug conjugates as well as polymeric micelle formulations. By incorporating an appropriate hydrophobic moiety to PGGA backbone, a novel series of PGGA-based polymer hydrotrope is created and utilized in producing stable paclitaxel-encapsulated polymeric micelles (PMs). A lead candidate, designated as NittoX, has been identified from a matrix of such PMs varying in encapsulated paclitaxel and conjugated hydrophobic moiety contents. For NittoX bioperformance, an outstanding anticancer efficacy is observed in NCI-H460 lung cancer xenograft. Dose response is evident and NittoX is able to completely suppress tumor growth at the dosage of 80 mg/kg. More importantly, NittoX is statistically significantly more efficacious than Abraxane at the same dose levels. Dosages are well tolerated by animals in terms of body weight loss and survival. In addition to NCI-H460, NittoX is also found efficacious in a variety of tumor models, including pancreatic cancer. The improved performance is even more evident when administrated with multiple-dose regimens. The improved efficacy is presumably attributed to its superior plasma and tumor pharmacokinetic profile. NittoX not only enhances circulation stability over Abraxane, but also demonstrates preferential tumor PK profile with three-fold elevation of Cmax and AUC(0-168h) as compared to Abraxane. Meanwhile, the results from pharmacodynamic analysis of tubulin polymerization alteration and consequent tumor cell proliferation inhibition are in accordance with in vivo tumor efficacy data. Strong correlation between tumor PK and PD is observed. These preclinical data undoubtedly suggest that NittoX has potential to become a more potent taxane nanomedicine superior to Abraxane. Citation Format: Wenbin Ying, Jihua Liu, Kwok Yin Tsang, Li Wang, Haiqing Yin, Hao Bai, Yuwei Wang, Liping Wang, Yoshiro Niitsu. A novel polymer-anticancer drug micelle formulation showing enhanced efficacy over Abraxane. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4578. doi:10.1158/1538-7445.AM2014-4578