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Mesothelin: An early detection biomarker for cancer (By Jack Andraka)

Author/ Curator:  Tilda Barliya PhD

I was recently amazed to read about a young teen who scooped the headlines with his story: Jack Andraka created an early detection test for pancreatic cancer (PC) (1). While we extensively discussed pancreatic cancer in previous posts (1b), this one deserve it’s on attention.

Andraka tells the audience about his journey from learning about a the  family member  diagnosed with PC, to a flash insight while learning about carbon nanotubes during a biology class, through the screening and finding one protein out of thousands and all the way up his final discovery. His journey wasn’t easy to say the least, he story though deserve all the applause.

Starting with his journey, Andraka began by “looking for a protein in the bloodstream that would be a biomarker for pancreatic cancer, one that would be found in all cases, even in the earliest stages”. He finally narrowed it down to the one that could work – Mesothelin.

So what is mesothelin?

Gubbels JA, et al. Mol. Cancer (2006). Model for peritoneal metastasis of ovarian tumors.

Mesothelin is a 4o kDa secreted protein expressed in normal mesothelial cells and over-expressed in several human tumors including mesothelioma, ovarian and pancreatic adenocarcinoma (2,3). Although the full mechanism by which mesothelin work is still unsolved, it is postulated thought, that mesothelin growth and apoptosis of pancreatic cancer cells by a p53 -dependent and independent pathways (7).

Andraka’s method:

human mesothelin-specific antibodies  were mixed with single walled carbon nanotubes and used to coat strips of ordinary filter paper. This made the paper conductive. The optimal layering was determined using a scanning electron microscope.  Cell media spiked with varying amounts of mesothelin was then tested against the paper biosensor and any change in the electrical potential of the sensor strip (due to the changing conductivity of the nanotubes) was measured, before and after each application.

The antibodies would bind to the mesothelin and enlarge. These beefed-up molecules would spread the nanotubes farther apart, changing the electrical properties of the network: The more mesothelin present, the more antibodies would bind and grow big, and the weaker the electrical signal would become.

A dose-response curve was constructed with an R2 value of .9992. Tests on human blood serum obtained from both healthy people and patients with chronic pancreatities, pancreatic intraepithelial neoplasia (a precursor to pancreatic carcinoma), or pancreatic cancer showed a similar response. The sensor’s limit of detection sensitivity was found to be 0.156 ng/mL; 10 ng/mL is considered the level of overexpression of mesothelin consistent with pancreatic cancer. Andraka’s sensor costs $0.03 (to compare to a $800 cost of a standard test) and 10 tests can be performed per strip, taking 5 minutes each. The method is 168 times faster, 26,667 times less expensive, and 400 times more sensitive than ELISA, and 25% to 50% more accurate than the CA19-9 test (5).

More so, Wang K and colleagues showed that inhibition of mesothelin may be used as novel strategy for targeting cancer cells (6). The authors showed that silencing the MSLN gene, encoding for mesothelin, inhibits cell proliferation and invasion. While this work is very impressive, the authors haven’t evaluated the potential use these siRNA in animal studies.

In summary:

It is very exiting to know that we may now have a simple and cheap blood test that has the huge potential to save many lives. All we need to do now is to conduct a multinational large scale screening for potential patients.

Andraka on his part is very hopeful, he believes  “it could potentially be used to test for ovarian and lung cancer too. And by switching out the protein the test reacts to, it could — down the road — be used for diseases as varied as heart disease and HIV/AIDS”.

Ref:

1. By: Kate Torgovnich . An early detection test for pancreatic cancer: Jack Andraka at TED2013.http://blog.ted.com/2013/02/27/an-early-detection-test-for-pancreatic-cancer-jack-andraka-at-ted2013/

1b. By; Tilda Barliya PhD. Pancreatic Cancer: Genetics, Genomics and Immunotherapy. http://pharmaceuticalintelligence.com/2013/04/11/update-on-pancreatic-cancer/

2. Mesothelin. http://en.wikipedia.org/wiki/Mesothelin

3. Nathalie Scholler. Mesothelin. http://www.med.upenn.edu/schollerlab/user_documents/Scholler%20Encyclopedia%20of%20Cancer%202008.pdf

4. Argani P, Iacobuzio-Donahue C, Ryu B, Rosty C, Goggins M, Wilentz RE, Murugesan SR, Leach SD, Jaffee E, Yeo CJ, Cameron JL, Kern SE and Hruban RH. Mesothelin is overexpressed in the vast majority of ductal adenocarcinomas of the pancreas: identification of a new pancreatic cancer marker by serial analysis of gene expression (SAGE). Clin Cancer Res. 2001 Dec;7(12):3862-3868. http://clincancerres.aacrjournals.org/content/7/12/3862.long

5. Jack Andraka and Glen Burnie, MD. A Novel Paper Sensor for the Detection of Pancreatic Cancer. http://apps.societyforscience.org/intelisef2012/project.cfm?PID=ME028&CFID=28485&CFTOKEN=10931553

6. Wang K, Bodempudi V, Liu Z, Borrego-Diaz E, Yamoutpoor F, et al. (2012) Inhibition of Mesothelin as a Novel Strategy for Targeting Cancer Cells. PLoS ONE 7(4): e33214. doi:10.1371/journal.pone.0033214. http://www.plosone.org/article/info:doi/10.1371/journal.pone.0033214

7.  Zheng C, Jia W, Tang Y, Zhao HL, Jiang Y and Sun S.  Mesothelin regulates growth and apoptosis in pancreatic cancer cells through p53-dependent and -independent signal pathway. Journal of Experimental & Clinical Cancer Research 2012, 31:84.  http://www.jeccr.com/content/pdf/1756-9966-31-84.pdf

Other related articles on this open Access Online Scientific Journal, include the following:

I. Pancreatic cancer genomes: Axon guidance pathway genes – aberrations revealed.

Aviva Lev-Ari, PhD, RN, 10/24/2012

http://pharmaceuticalintelligence.com/2012/10/24/pancreatic-cancer-genomes-axon-guidance-pathway-genes-aberrations-revealed/

II. Biomarker tool development for Early Diagnosis of Pancreatic Cancer: Van Andel Institute and Emory University.

Aviva Lev-Ari PhD,RN, 10/24/2012

http://pharmaceuticalintelligence.com/2012/10/24/biomarker-tool-development-for-early-diagnosis-of-pancreatic-cancer-van-andel-institute-and-emory-university/

III. Personalized Pancreatic Cancer Treatment Option.

Aviva Lev-Ari PhD, RN, 10/16/2012

http://pharmaceuticalintelligence.com/2012/10/16/personalized-pancreatic-cancer-treatment-option/

IV. Battle of Steve Jobs and Ralph Steinman with Pancreatic cancer: How we lost.

Ritu Saxena PhD, 5/21/2012

http://pharmaceuticalintelligence.com/2012/05/21/battle-of-steve-jobs-and-ralph-steinman-with-pancreatic-cancer-how-we-lost/

V.  Early Biomarker for Pancreatic Cancer Identified.

Prabodh Kandala, PhD, 5/17/2012

http://pharmaceuticalintelligence.com/2012/05/17/early-biomarker-for-pancreatic-cancer-identified/

VI. Usp9x: Promising therapeutic target for pancreatic cancer.

Ritu Saxen PhD, 5/14/2012

http://pharmaceuticalintelligence.com/2012/05/14/promising-therapeutic-target-discovered-for-pancreatic-cancer/

VII. Issues in Personalized Medicine in Cancer: Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing.

Stephen J. Williams, PhD, 10/4/2013

http://pharmaceuticalintelligence.com/2013/04/10/issues-in-personalized-medicine-in-cancer-intratumor-heterogeneity-and-branched-evolution-revealed-by-multiregion-sequencing/

VIII. In Focus: Targeting of Cancer Stem Cells.

Ritu Saxena, PhD, 3/27/2013

http://pharmaceuticalintelligence.com/2013/03/27/in-focus-targeting-of-cancer-stem-cells/

IIX. New Ecosystem of Cancer Research: Cross Institutional Team Science.

Aviva Lev-Ari. PhD, RN, 3/24/2013

http://pharmaceuticalintelligence.com/2013/03/24/new-ecosystem-of-cancer-research-cross-institutional-team-science/

IX. In Focus: Identity of Cancer Stem Cells.

Ritu Saxena, PhD, 3/22/2013

http://pharmaceuticalintelligence.com/2013/03/22/in-focus-identity-of-cancer-stem-cells/