17: Mitomycin C and Ganetespib in HIPEC: A novel drug combination for the treatment of peritoneal carcinomatosis disseminated from colon cancer in a syngeneic animal model.

Cyto-Reductive Surgery (CRS) with HIPEC has been a successful treatment for patients with Peritoneal Carcinomatosis (PC). Here, our aim was to establish an animal model of PC of colorectal origin and to test a novel drug combination in HIPEC to evaluate overall survival (OS).



Methods:

In vitro experiments were done using HT29 and HCT116 human cell lines. WAG/Rij rats were injected intraperitoneally with the CC531 colon cancer cell line. In 7 days, animals underwent survival surgery consisting of CRS/HIPEC. Briefly, a midline abdominal incision was made and the greater omentum, containing most peritoneal tumors, was resected with bipolar electrocauterization. Limited cauterization was performed in the lesser sac and around the porta hepatis to avoid injury to vital structures. For HIPEC, an outflow drain catheter was first inserted through the right flank and placed in the lower abdominal cavity. An inflow catheter was inserted through the left flank upward toward the liver. The abdominal wall was then closed in two layers and chemoperfusate containing either Mitomycin C (MMC), Ganetespib (GAN), a combination of both, or perfusate alone was infused into the abdomen via infusion pump at 42°C for 90 min.



Results:

In the absence of treatment, the pathogenesis of PC in our syngeneic model results in morbidity and mortality within 30-32 days post-inoculation with CC531 cells. The overall survival (OS) of our control group (n=6) infused with vehicle (perfusate) is consistent with this (33 ± 1.3). Rats treated with GAN (n=6) showed increased OS (37.5 ± 3.3) compared to control (33 ± 1.3) although this was not significant. Animals treated with MMC (n=6) showed a significant increase (p < 0.05) in OS (41.5 ± 4.4) versus control (33.8 days ± 1.3). Rats treated with a combination of MMC and GAN (n=5) also demonstrated a significant increase (p < 0.05) in OS (45.6 ± 5.8) compared to control (33 ± 1.3); however, MMC and GAN combination therapy was not significantly different than MMC monotherapy.


Conclusions: In this first in the US animal model, HIPEC combination therapy using MMC and the Heat Shock Protein-90 Inhibitor, Ganetespib, significantly increased OS in a pre-clinical animal model of PC. This data is supported by our in vitro evidence in human colon cancer cell lines showing decreased cell viability with combination therapy under hyperthermic conditions compared to controls. The use of Mitomycin C and Ganetespib together during HIPEC has shown efficacy in our model and needs further investigation to bring this promising treatment into the clinic.