Gastric cancer is the number three cause of death from cancer in the world, and the 15th most common cancer in the U.S. The main reason for poor outcomes with gastric cancer is that there are few symptoms in the early stages, so patients are often not diagnosed until the disease is advanced. Standard drug therapies for gastric cancer include platinum-based combination chemotherapy and monoclonal antibodies. However, the five-year survival rate for newly diagnosed cancers was only 29.3 percent between 2006 and 2011. There is a great unmet need for new targets and treatment strategies in gastric cancer.
Recent genomic studies have revealed mutations in the GTPase RHOA that are present in gastric cancer in humans. The RHOA signaling pathway activates a number of downstream effectors, including RHO-associated protein kinases 1 and 2 (ROCK 1/2). Through this pathway, RHOA helps to regulate cellular functions like growth and invasion–movement of cells into neighboring tissues. Could ROCK 1/2 be a significant target for gastric cancer drug development?
Isabel Hinsenkamp and colleagues studied a ROCK 1/2 inhibitor, fasudil, to see whether it was effective against gastric cancer in mice.
Hisenkamp examined stomach and liver tissue from transgenic mice with gastric carcinoma using the UltrafleXtreme MALDI-TOF/TOF mass spectrometer by Bruker Daltonik equipped with a 2000 Hz Smartbeam-II laser. The group also carried out Fourier transform ion cyclotron resonance MS at Bruker Daltonik on a 12 T solariX instrument equipped with an ESI/MALDI ion source.
The MALDI/MS studies showed that fasudil and its pharmacologically active metabolite hydroxyfasudil accumulated rapidly in the liver and were present in all anatomical stomach regions. There was no significant accumulation of the drug in the tumor compared to surrounding tissue, but the study showed that the drug distributed to the tumor in significant quantities. The MALDI-FTICR studies identified a specific translatable biomarker for gastric cancer in mouse.
Hisenkamp’s group followed up with a PET/CT study using the Bruker Albira II small-animal PET/SPECT/CT instrument to determine efficacy of fasudil against gastric tumors in mice. They dosed the mice at 10 mg/kg per day, four times per week, for four weeks, and found evidence that cancer cells were dying with reduction in tumor size. The location of the tumor was determined by overlaying images of the live treated and control animals. The control animals did not emit any signal in the anatomical area of the tumor. After sacrifice, closer PET/CT examination of the tissues demonstrated a decrease in the size of the tumor and reduction in the number of proliferating gastric tumor cells.
PET/CT imaging offers some advantages in preclinical drug studies because of its high sensitivity and superior temporal and spatial resolution capabilities. Typically, a therapeutic is matched with a suitable radionucleotide for detection. In this case, [18F]-Fluorodeoxyglucose (FDG), was used as a radioactive tracer.
Further study is needed to determine whether fasudil, a first-in-class ROCK 1/2 inhibitor, could be developed as a therapy for gastric cancer. The powerful combination of imaging methods, including MALDI-TOF/TOF, MALDI-FTICR imaging, and PET/CT scanning extracted results from a single experiment that in the past would have required a series of studies using separate methods for each experimental objective.
Hinsenkamp, I., Schulz, S., Roscher, M., Suhr, A., Meyer, B., Munteanu, B., . . . Burgermeister, E. (2016). Inhibition of Rho-Associated Kinase 1/2 Attenuates Tumor Growth in Murine Gastric Cancer. Neoplasia, 18(8), 500-511. doi:10.1016/j.neo.2016.07.002