MUC16 as a novel target for cancer therapy

Abstract

MUC16 is overexpressed in multiple cancers and plays an important role in tumorigenicity and acquired resistance to therapy. Area covered: In this review, we describe the role of MUC16 under normal physiological conditions and during tumorigenesis. First, we provide a summary of research on MUC16 from its discovery as CA125 to present anti-MUC16 therapy trials that are currently in the initial phases of clinical testing. Finally, we discuss the reasons for the limited effectiveness of these therapies and discuss the direction and focus of future research. Expert opinion: Apart from its protective role in normal physiology, MUC16 contributes to disease progression and metastasis in several malignancies. Due to its aberrant overexpression, it is a promising target for diagnosis and therapy. Cleavage and shedding of its extracellular domain is the major barrier for efficient targeting of MUC16-expressing cancers. Concerted efforts should be undertaken to target the noncleaved cell surface retained portion of MUC16. Such efforts should be accompanied by basic research to understand MUC16 cleavage and decipher the functioning of MUC16 cytoplasmic tail. While previous efforts to activate anti-MUC16 immune response using anti-CA125 idiotype antibodies have met with limited success, ideification of neo-antigenic epitopes in MUC16 that correlate with improved survival have raised raised hopes for developing MUC16-targeted immunotherapy.

Keywords: MUC16; cancer therapy; immunotherapy; mucins; targeted therapy.

Figure 1:

Timeline depicting the significant discoveries related to MUC16 biology and therapy: MUC16 was first discovered as CA125 in Ovarian Cancer antigen in 1981. CA125 soon was found to be a biomarker for ovarian cancer and was capable of predicting recurrence and progression of the disease. Soon its utility as an immunotherapy agent was tested that resulted in the first radio immunotherapy trials in 1989. By 1995–1998, naked anti-CA125 antibodies and anti-idiotype antibodies (vaccines) were tested in ovarian cancer patients. Both resulted in the generation of potent idiotype network resulting in the robust anti-CA125 immune response. However, overall survival was not improved to a large extent. By 2001, cloning of CA125 structure revealed it to belong to mucin family and was named mucin MUC16. By 2004, a significant interaction of MUC16 with mesothelin was discovered that helped in the peritoneal metastasis of ovarian cancer cells to the abdomen. In 2007, the first antibody-drug conjugate and in 2010 the primary CAR-T cells were developed that target MUC16. In 2016, phase 1 clinical trial of the ADC showed preliminary efficacy.

Figure 2:

Schematic representation of MUC16 structure: MUC16 contains three domains: The N-terminal domain (~12000 amino acids in length), tandem repeat domain which is interspersed with SEA domain and the C-terminal domain. The Tandem Repeat (TR) domain contains 18–60 repeats each with ~156 amino acids and has ankyrin (ANK) 1 and 2 sites along with the SEA domains. The C-terminal domain is further divided into an extracellular portion, which contains the putative cleavage site, a transmembrane domain and a cytoplasmic tail of 32 amino acid length. The cytoplasmic tail contains an ERM binding domain and a putative nuclear localization signal (RRRKK).