Crystal structure of a human MUC16 SEA domain reveals insight into the nature of the CA125 tumor marker

White, Brandy; Patterson, Michelle; Karnwal, Saloni; Brooks, Cory L.

doi:10.1002/prot.26303

Cited by 17 publications

(11 citation statements)

References 41 publications

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“…To carry out binding studies, a MUC16 fragment corresponding to tandem repeat 5 (TR5) and flanking residues from TR4 and TR6 (Uniprot code, Q8WXI7, residues 12665−12857) was expressed in E. coli as a thioredoxin (Trx)-fusion and purified to homogeneity by immobilized metal affinity chromatography as described previously. 25 Binding of murine, chimeric, and humanized antibody and antibody conjugates to recombinant MUC16 was assessed with an ELISA in which a 96 well plate (Fisher Scientific, 21-377-203; Waltham, MA) was coated overnight at 4 °C with recombinant MUC16 antigen (100 ng of Trx-TEV-TR6-SEA5-TR4 in PBS). The plate was blocked with bovine serum albumin (BSA; 1% in PBS, 1 h, room temperature).…”

Section: ■ Materials and Methodsmentioning

confidence: 99%

Preclinical Evaluation of a Humanized, Near-Infrared Fluorescent Antibody for Fluorescence-Guided Surgery of MUC16-Expressing Pancreatic Cancer

et al. 2022

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Surgery remains the only potentially curative treatment option for pancreatic cancer, but resections are made more difficult by infiltrative disease, proximity of critical vasculature, peritumoral inflammation, and dense stroma. Surgeons are limited to tactile and visual cues to differentiate cancerous tissue from normal tissue. Furthermore, translating preoperative images to the intraoperative setting poses additional challenges for tumor detection, and can result in undetected and unresected lesions. Thus, pancreatic ductal adenocarcinoma (PDAC) has high rates of incomplete resections, and subsequently, disease recurrence. Fluorescence-guided surgery (FGS) has emerged as a method to improve intraoperative detection of cancer and ultimately improve surgical outcomes. Initial clinical trials have demonstrated feasibility of FGS for PDAC, but there are limited targeted probes under investigation for this disease, highlighting the need for development of additional novel biomarkers to reflect the PDAC heterogeneity. MUCIN16 (MUC16) is a glycoprotein that is overexpressed in 60–80% of PDAC. In our previous work, we developed a MUC16-targeted murine antibody near-infrared conjugate, termed AR9.6–IRDye800, that showed efficacy in detecting pancreatic cancer. To build on the translational potential of this imaging probe, a humanized variant of the AR9.6 fluorescent conjugate was developed and investigated herein. This conjugate, termed huAR9.6–IRDye800, showed equivalent binding properties to its murine counterpart. Using an optimized dye:protein ratio of 1:1, in vivo studies demonstrated high tumor to background ratios in MUC16-expressing tumor models, and delineation of tumors in a patient-derived xenograft model. Safety, biodistribution, and toxicity studies were conducted. These studies demonstrated that huAR9.6–IRDye800 was safe, did not yield evidence of histological toxicity, and was well tolerated in vivo. The results from this work suggest that AR9.6-IRDye800 is an efficacious and safe imaging agent for identifying pancreatic cancer intraoperatively through fluorescence-guided surgery.

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Section: ■ Materials and Methodsmentioning

confidence: 99%

Preclinical Evaluation of a Humanized, Near-Infrared Fluorescent Antibody for Fluorescence-Guided Surgery of MUC16-Expressing Pancreatic Cancer

et al. 2022

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“…Increase in CA 125 levels can be used to detect the development of benign tumors into malignant tumors. Enhanced CA 125 levels are also used to identify treatment failure as well as disease recurrence (e.g., high CA 125 levels after bilateral salpingo-oophorectomy or total abdominal hysterectomy, which may occur after first line chemotherapy) [ 116 , 117 , 118 , 119 , 120 ]. Altogether, CA 125 is an extremely essential biomarker for detection of cancer, and also for cancer progression monitoring and treatment.…”

Section: Cancer Biomarkersmentioning

confidence: 99%

Recent Trends in Biosensing and Diagnostic Methods for Novel Cancer Biomarkers

et al. 2023

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Cancer is one of the major public health issues in the world. It has become the second leading cause of death, with approximately 75% of cancer deaths transpiring in low- or middle-income countries. It causes a heavy global economic cost estimated at more than a trillion dollars per year. The most common cancers are breast, colon, rectum, prostate, and lung cancers. Many of these cancers can be treated effectively and cured if detected at the primary stage. Nowadays, around 50% of cancers are detected at late stages, leading to serious health complications and death. Early diagnosis of cancer diseases substantially increases the efficient treatment and high chances of survival. Biosensors are one of the potential screening methodologies useful in the early screening of cancer biomarkers. This review summarizes the recent findings about novel cancer biomarkers and their advantages over traditional biomarkers, and novel biosensing and diagnostic methods for them; thus, this review may be helpful in the early recognition and monitoring of treatment response of various human cancers.

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“…In a large investigation of lung cancer, MUC16 gene mutations were found in 53 percent of cases, including 51 percent of adenocarcinoma and 56 percent of squamous cell carcinoma [ 49 ]. MUC16 was considered one of three genes with the greatest frequency of mutations across a variety of cancers [ 50 ]. The high MUC16 expression caused by gene mutations affected cell proliferation, migration, and invasion in cultured lung cancer cells in this work.…”

Section: Muc16 (Ca 125) and Malignant Proliferationmentioning

confidence: 99%

The Potential Role of MUC16 (CA125) Biomarker in Lung Cancer: A Magic Biomarker but with Adversity

et al. 2022

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Lung cancer is the second most commonly diagnosed cancer in the world. In terms of the diagnosis of lung cancer, combination carcinoembryonic antigen (CEA) and cancer antigen 125 (CA125) detection had higher sensitivity, specificity, and diagnostic odds ratios than CEA detection alone. Most individuals with elevated serum CA125 levels had lung cancer that was either in stage 3 or stage 4. Serum CA125 levels were similarly elevated in lung cancer patients who also had pleural effusions or ascites. Furthermore, there is strong evidence that human lung cancer produces CA125 in vitro, which suggests that other clinical illnesses outside of ovarian cancer could also be responsible for the rise of CA125. MUC16 (CA125) is a natural killer cell inhibitor. As a screening test for lung and ovarian cancer diagnosis and prognosis in the early stages, CA125 has been widely used as a marker in three different clinical settings. MUC16 mRNA levels in lung cancer are increased regardless of gender. As well, increased expression of mutated MUC16 enhances lung cancer cells proliferation and growth. Additionally, the CA125 serum level is thought to be a key indicator for lung cancer metastasis to the liver. Further, CA125 could be a useful biomarker in other cancer types diagnoses like ovarian, breast, and pancreatic cancers. One of the important limitations of CA125 as a first step in such a screening technique is that up to 20% of ovarian tumors lack antigen expression. Each of the 10 possible serum markers was expressed in 29–100% of ovarian tumors with minimal or no CA125 expression. Therefore, there is a controversy regarding CA125 in the diagnosis and prognosis of lung cancer and other cancer types. In this state, preclinical and clinical studies are warranted to elucidate the clinical benefit of CA125 in the diagnosis and prognosis of lung cancer.

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Crystal structure of a human MUC16 SEA domain reveals insight into the nature of the CA125 tumor marker

Cited by 17 publications

References 41 publications

Preclinical Evaluation of a Humanized, Near-Infrared Fluorescent Antibody for Fluorescence-Guided Surgery of MUC16-Expressing Pancreatic Cancer

Preclinical Evaluation of a Humanized, Near-Infrared Fluorescent Antibody for Fluorescence-Guided Surgery of MUC16-Expressing Pancreatic Cancer

Recent Trends in Biosensing and Diagnostic Methods for Novel Cancer Biomarkers

The Potential Role of MUC16 (CA125) Biomarker in Lung Cancer: A Magic Biomarker but with Adversity

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