The first phase I trials (NCT01279603) to test GO-203-2c (Genus Oncology, LLC), a newly discovered and optimized peptide to target MUC 1compound that binds to an oncoprotein called MUC1 has started in patients with solid tumors. MUC1 is over-expressed in 80-90% of all solid tumors and many hematologic cancers, including breast, prostate, lung, colon, pancreas and ovarian that have been associated with poor prognosis. By binding to MUC1, GO-203-2c eventually causes tumor cell death in laboratory studies.
Of an estimated 1.4 million cancer cases diagnosed each year in the US, about 900,000 over-express MUC1, thus making it an attractive target for developing anti-cancer drugs. To date, there are no approved agents that target MUC1.
While not generally recognized as effectors of carcinogenesis, researchers have found that mucins are intimately involved in inflammation and cancer. This finding has provided the experimental basis for GO-203-2c, demonstrating that inhibitors of their function are effective as anti-tumor agents in preclinical models.
Normal Physiological Function of MUC1
MUC1 proteins, commonly described as hair-like filaments extending on the apical exterior of an epithelial cell, provides a protective barrier for the outer surface of epithelial cells on the inner surface of the intestine and other organs. This barrier protects the body from infection by binding to pathogens. MUC1 also prevents caustic elements, such as toxins, free radicals, acids and other forms of cell stress from having direct contact with the epithelial cell. Under stress, the exterior portion of the MUC1 protein breaks away. This phenomenon is known as cleavage, and the resulting protein fragments as shed ectodomain.
Mechanism of Action
MUC 1 also extends across the cell membrane into the cell itself. The intracellular portion of MUC1 plays a key role in the signaling that increases cell growth activity and protects against cell death. Researchers have found that a variety of cancers exploit this secondary role by overexpressing MUC1, which dramatically increases cell growth conditions and blocks the cell death pathways generally used by common anti-cancer drugs.
The mechanism of action of GO-203-2c has been identified, and in vitro and in vivo studies have confirmed that the new this investigational drug candidate has significant and prolonged antitumor activity in MUC1 expressing tumors.
A Different Approach
In contrast to many development programs involving MUC1, which are generally focusing on peptide vaccines and antibodies targeting the MUC1 ectodomain, researchers involved with the development of GO-203-2c are focusing on the MUC1 protein segment inside the cell, the intracellular domain.
Phase I trial
Commenting on the beginning of the trial, Stephen Thompson, CEO and President of Genus Oncology, said: “We are excited to enter this new phase of clinical development. Filing the Investigational New Drug (IND) application with the US Food & Drug Administration (FDA) represents the culmination of years of innovation and hard work by Genus Oncology’s scientific and development teams. Our work demonstrates that Mucin 1 (MUC1) is a viable drug target, and that inhibition of MUC1 function blocks tumor development and survival of multiple human cancers in preclinical models, including breast, prostate, colon, lung, and pancreatic cancers. Across multiple animal models of human tumor xenografts, treated animals experienced complete responses and remained tumor free up to 6 months post treatment. We look forward to leveraging our understanding of the role of MUC1 in cancer, and taking the first step to advance the treatment of cancer through Phase I clinical trial and follow-on development programs.”
“The basic science behind this is a brilliant piece of work. We are very pleased to translate this into new therapeutics for patients,” said Dr. Daniel Von Hoff, Physician in Chief, Distinguished Professor, Translational Genomics Research Institute (TGen), Professor of Medicine, Mayo Clinic, Clinical Professor of Medicine, University of Arizona College of Medicine and Chief Scientific Officer, Scottsdale Healthcare and US Oncology Research, and Principle Investigator for the Phase I study.
The Phase I trial is a prospective, open-label study that is designed to determine the safety and tolerability, and potential anti-tumor activity of Genus’ first drug candidate, GO-203-2c. Up to 40 patients will be enrolled in the study at multiple clinical sites. The sites currently contracted to conduct the Phase I trial are the University of Texas Health Science Center at San Antonio (UTHSCSA) and the Virginia G. Piper Cancer Center at Scottsdale Healthcare Hospital. Additional sites are currently under consideration.
The primary goals for the trial are to determine the maximum tolerated dose (MTD) and identify the dose limiting toxicities (DLT) of GO-203-2c. The trial results will also help to establish the dose of GO-203-2c recommended for future phase II protocols.
“We are very enthusiastic to participate in this clinical trial with a promising and innovative targeted therapy. We are excited to have identified the first patient to be treated in the study and will work diligently together with our colleagues from TGen as well as with our partners from Genus to achieve the study goals,” said Dr. Alain Mita, Director of the Advanced Fellowship Program in Drug Development at UTHSCSA.
“We are excited to work with a distinguished team at Genus Oncology and Harvard Medical School,” said Dr. Ramesh Ramanathan, Medical Director, TGen Clinical Research Services at Scottsdale Healthcare. “In normal cells MUC1, a mucin, coats the intestine and other organs and prevents penetration of bacteria and other pathogens. The MUC1 protein is abnormal and present in high concentrations in cancer cells and appears to be important in cancer cell growth; and GO-203-2c is one of the first peptides to specifically target this molecule.”
For more information:
NCT01279603 Study of GO-203-2C Given Intravenously in Patients With Advanced Solid Tumors
Yin L, Ahmad R, Kosugi M, Kufe T, Vasir B, Avigan D, Kharbanda S, Kufe D. Survival of human multiple myeloma cells is dependent on MUC1 C-terminal transmembrane subunit oncoprotein function. Mol Pharmacol. 2010 Aug;78(2):166-74. Epub 2010 May 5.
Kufe DW. Mucins in cancer: function, prognosis and therapy. Nat Rev Cancer. 2009 Dec;9(12):874-85. Full Article.