Growth inhibitory effect of PHRAD129, a Higher Order Therapeutics (HOT) drug derived from Curcuma longa, in SCCVII head and neck cancer syngeneic mouse xenograft tumor model system

Presentation: P003
Topic: Cancer Biology
Type: Poster
Authors: Daniel S Shin, MD, PhD1; Saroj Basak, PhD2; Mysore S Veena, PhD2; Tien S Dong, MD, PhD1; Jonathan P Jacobs, MD, PhD1; Chan Jeong, BS2; Luis Z Avila, PhD3; Eri S Srivatsan, PhD2; Marilene B Wang, MD1
Institution(s): 1UCLA; 2VA Greater Los Angeles Healthcare System; 3Aveta Biomics, Inc.

Our recent phase I clinical study of APG-157, a higher order therapeutic (HOT) drug containing curcumin, in normal and head and neck cancer subjects showed an excellent safety profile, inhibitory effect on cancer-associated cytokines, alteration of the oral microbiota and a marked increase in CD4 and CD8 positive T cell infiltration into the tumor microenvironment. Based on these observations, we performed in-vitro growth studies on the head and neck cancer cell line UM-SCC1 and preclinical evaluation of SCCVII tumor cell line growth in a syngeneic mouse xenograft tumor model. We used PHRAD129, the drug substance used in formulating APG-157. In the UM-SCC1 cells, the treatment with PHRAD129 showed inhibition of expression of p-IkB and cyclin D1, indicating an inhibitory effect on NFkB. In the mouse model system, delivering PHRAD129 in food (1% w/w in normal mouse chow), water (2.5mg/ml for 7 days and 10mg/ml for 3 more weeks, also containing 0.5% sucrose to compensate for the taste),  or IP (intra-peritoneal injection 5 days a week of 0.5mg in 200ul pharmaceutical grade saline/mouse for 1 week and 1.0mg in 200ul saline/mouse for 3 more weeks) showed tissue absorption of curcumin and its derivatives in the serum of mice fed with 1% PHRAD129 in the normal mouse diet. Further, mice fed with 1, 2 and 4% PHRAD129 diet did not show blood toxicity and there was a higher level of curcumin and derivatives in the serum of mice fed with 2 and 4% PHRAD diet. Microbial content through16S RNA seq analysis of mouse fecal material showed the greatest alpha diversity from 1% to 2% PHRAD, with 2% and 4% PHRAD129 being similar in both alpha diversity and microbial genetic makeup. There was a significant decrease in Lactobacillus species and an increase in Lachnospiracea NK4A136 species in 2 and 4% PHRAD129 fed mice in comparison to the 1% PHRAD diet. A preliminary study of one month feeding followed by SCCVII xenograft tumor cell injection showed inhibition of tumor growth in the 4% diet. Additional studies are required to confirm tumor cell growth inhibition by 4% PHRAD129 diet and draw conclusions on the relationship between gut microbial changes and in vivo tumor cell growth inhibition.