It sounds counterintuitive, but targeting a neuropeptide hormone produced in the hypothalamus may be an effective strategy for treating gastric cancer, the second most common cause of cancer deaths worldwide, investigators from China and the United States contend.
Growth hormone–releasing hormone (GHRH) and its receptor (GHRH-R) are found primarily in the anterior pituitary gland, but are also present in gastric cancers, other solid tumors, and lymphomas. Increased levels of GHRH-R in tumor samples from patients with gastric cancer are associated with poor outcomes, noted Andrew V. Schally, PhD, MD, DSc, of the University of Miami, and his colleagues at the Shantou (China) University Medical College.
Furthermore, an experimental peptide drug labeled MIA-602 that targets GHRH-R inhibited the growth of gastric cancer cell lines and human tumor xenografts in mice, the investigators reported in the journal PNAS.
“The GHRH receptor is both a biomarker that can confirm prognosis and a therapeutic target,” Dr. Schally said in a statement.
Elevated GHRH-R expression in tumors
GHRH-R antagonists such as MIA-602 work through downregulation of the p21-activated kinase 1 (PAK1)–mediated signal transducer and activator of transcription 3 (STAT3)/nuclear factor–kappaB (NF-kappaB) inflammatory pathway. This pathway is involved in the interplay between inflammatory processes and intracellular signaling thought to be the cause of gastric cancer tumorigenesis and progression, the investigators explained.
They first looked for GHRH-R expression in gastric cancer samples from 106 patients, using immunohistochemistry staining of primary tumors and adjacent normal tissues. They found that gastric cancer tissues “exhibited robust expression of GHRH-R, compared with normal tissues.”
In 50 samples, GHRH-R was determined to be overexpressed, and this overexpression was significantly associated with both greater tumor size (P = .031) and high pathologic tumor stage (P = .001). Increasing expression of GHRH-R was also significantly associated with worse overall survival (P less than .001).
They confirmed these findings in samples from a multinational cohort of patients, which again showed that the highest levels of GHRH-R expression were associated with poor overall survival (P less than .001).
The authors also looked at messenger RNA expression and gene copy number in 65 gastric cancer samples and 19 adjacent normal tissue samples, and found that GHRH-R mRNA was significantly higher in tumor tissues than normal control tissues (P less than .001).
MAI-602 in vitro and in vivo
To see whether MAI-602 could inhibit the growth of gastric cancer cells, the investigators tried it at various doses in three human gastric cancer cell lines, and found that it inhibited cells in a dose-dependent fashion, compared with vehicle used as a control (P less than .001).
In addition, the experimental agent “exhibited remarkable inhibitory effects on tumor growth in vivo” in mice with human tumor xenografts (P less than .001).
Finally, they showed that the cancer suppression effects of MAI-602 work through inhibition of STAT3/NF-kappaB inflammatory signaling. In vitro and in vivo, MAI-602 decreased the expression of both GHRH and GHRH-R, whereas as a GHRH-R agonist increased levels of both the hormone and its receptor. They also demonstrated that PAK1 appears to be a critical mediator of STAT3/NF-kappaB activity, and that MAI-602 works primarily by blocking PAK1-mediated inflammatory signaling.
“MIA-602 remarkably inhibits the growth of human in vitro and in vivo through the suppression of PAK1–STAT3/NF-kappaB signaling. Our study strongly highlights the therapeutic potential of GHRH-R antagonists in the treatment of gastric cancer patients. Knowledge gained in our study will shed light on how to select the appropriate patients for personalized cancer therapy using GHRH-R antagonists,” Dr. Schally and his coauthors wrote.
The study was supported by the Li Ka Shing Foundation, Chinese foundation, and government grants to individual researchers, as well as support from the the Medical Research Service of the U.S. Department of Veterans Affairs, South Florida Veterans Affairs Foundation for Research and Education, and the University of Miami.