New Spin on Pancreatic Cancer Diagnostics

Neeley Remmers

Recently, 15-year old Jack Andraka made national headlines for the diagnostic assay he created to detect pancreatic cancer. Before I get into discussing the science behind his assay, let me first give Jack a major shout-out for having the courage to pursue his idea in the first place. He gave a presentation of his theory to 200 professors at Johns Hopkins University, a feat that would terrify most of us even after having graduated with our PhD let alone at the age of 15. He impressed Dr. Anirban Maitra, a world-renowned pathologist and scientist in pancreatic cancer, and gained an invitation into Dr. Maitra’s lab to work on his idea. Jack’s motivation to design a diagnostic assay for pancreatic cancer because his uncle died from the disease.

For those of you who don’t know the field, there currently is no effective way to diagnose pancreatic cancer, especially when it is in its earliest stages. There are a number of reasons for this – clinical symptoms do not present themselves until the disease has progressed to metastasis at which point makes it very hard to treat, most symptoms are typically any combination of abdominal pain, back pain,  jaundice and weight loss which can be the cause of any number of diseases, and due to the anatomical position of the pancreas it is very hard to image making it difficult to use standard imaging techniques to screen for early lesions like you can with breast cancer. As you can see, the need for a blood-based or other bodily-fluid based screening test is huge to adequately diagnose pancreatic cancer. Many scientists and physicians have been diligently working on this issue for a number of years, myself included, and have generated multiple platforms to use for early diagnosis including Dr. Brian Haab’s antibody-lectin arrays (the most recent publication being Cao Z et al. Mol Cell Proteomics 2013), Dr. Clausen and Dr. Blixt’s glycopeptide arrays to detect auto-antibodies (Pedersen JW et al. Int J Cancer  2011, Blixt O et al J Proteome Res 2010), and conjugating antibodies to Qdots, sphero beads, nanotubes and other fluorescent tags. The reasoning behind conjugating the antibody that recognizes your biomarker of choice is that fluorescence provides greater sensitivity than colorimetric assays that rely on the enzymatic cleavage of DAB or ABTS, for example. All these platforms are innovative and effective in their own right, but the real trick to designing an efficacious diagnostic assay is choosing the right biomarker to detect. This is where things get messy in the field of pancreatic cancer diagnostics.

Since very few patients are diagnosed in the early stages of pancreatic cancer, there is a very limited supply of samples from the early lesions, which are called PanINs. In fact, a large portion of the PanINs actually studied were pulled out of tumors from patients that had advanced disease, so you have to be really careful with conclusions drawn from these “PanINs” since we don’t know if they behave the same as true PanINs that arise prior to malignancy. Therefore, at this point in time, we are limited to studying the vast number of secreted proteins that can be found in blood, plasma, or urine of advanced pancreatic cancer patients. There are a limited number of studies (I know of 2 done in the UK) where blood samples were collected from patients over 20+ years in which a portion of these patients developed pancreatic cancer, and these samples are available for use in retrospective studies to see if the protein chosen to be used as a biomarker for pancreatic cancer is found in these patients early on when they would have presumably had early-stage disease. As you can see, there are a lot of challenges in this field that can make it rather daunting, and more often than not the biomarkers chosen to be used for diagnosis end up failing.

What did Jack Andraka do, other than being a 15-year old studying this challenging field, to make such a splash in the headlines? The platform Jack designed is unique in that he chose to attach his nanotube-conjugated antibodies to nothing other than filter paper making his platform the cheapest one yet. The biomarker he has chosen to detect in the bodily-fluids from patients is mesothelin. Mesothelin has been investigated as a potential biomarker of pancreatic cancer since at least 2004, but has yet to be shown to truly be better than all the other potential pancreatic cancer biomarkers. Jack’s test is still in preliminary stages so we have yet to see how efficacious it really is at diagnosing pancreatic cancer early on. Additionally, utilizing nanotubes conjugated to antibodies is not new either. In fact, a student in one of our collaborating labs at my university was doing the exact same thing 5 years ago; however, because we did not have an instrument on campus that would allow him to detect the nanotubes, he had to drop the project. What does make Jack’s platform unique is he linked his nanotubes to nothing more than filter paper instead of a more expensive spotted plate making his assay the cheapest one yet. The biggest flaw in Jack’s design is that it relies entirely on the detection of a single biomarker. It is pretty well-known and accepted in the field that in order to have a highly specific, effective diagnostic test you need to assay for a panel of established biomarkers that can distinguish pancreatic cancer from other benign and malignant diseases. Thus, he may need to go back to the drawing board to determine which panel of biomarkers perform the best in detecting pancreatic cancer. However, I do think his platform shows promise and will soon turn into a clinically useful early diagnostic assay.

 

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