On average, only 45 percent of Canadians regularly go to the doctor for complete physicals or checkups. In between these checkups, most of us only seek medical attention if we notice that something is amiss. But what if symptoms are not noticeable? Often, tumours are not found or diagnosed until symptoms are so severe that standard treatments simply do not work. This conundrum of late detection is where the stories of many cancer researchers start, including those at Stanford’s Canary Center for Cancer Early Detection.
According to the World Health Organization, the consequences of delays in cancer treatment are dire, with the likelihood of death from cancer increasing significantly as cancer progresses. But how can we detect these cancers at stage 1 – or even before that – when there are only a few thousand cancer cells, as opposed to a billion cells in a noticeable lump? In the Canary Center’s vision, driven specifically by Dr. Sanjiv S. Gambhir, to detect cancer early we would monitor the human body all the time. According to Gambhir, this futuristic ideal includes the use of everything from implanted devices that initiate daily blood tests to a toilet that checks your urine for biomarkers. While these possibilities may sound light-years away, Gambhir’s team at Standford is already moving into the future, pioneering stunning technologies that include non-viral tumour-activatable minicircles (MC) and the use of ultrasound waves to better detect both exogenous and endogenous cancer biomarkers.
Currently, one of the most promising detection methods involves identifying endogenous cancer biomarkers in the blood, such as proteins, DNA and microRNA that the growing and dying tumour cells shed into the bloodstream. However, this technology has its limitations, including tumour heterogeneity and the time it takes for the tumour itself to begin shedding these biomarkers. To overcome these limitations, the Gambhir research group designed a strategy based on tumour-activatable MC, which use a tumour-specific promoter to drive expression of a reporter protein that is secreted into the blood. The reporter protein used, SEAP, is driven by the promoter for the tumour-specific molecule Survinin (BIRC5), which is a member of the apoptotic inhibitor family and helps control mitotic progression and prevent cell death. This promoter has been identified in many cancers, including melanoma, liver, lung, breast and colon cancer, but is not expressed at detectable levels in healthy adults, making it an ideal choice of biomarker. The technique has already shown promise in mice and the team envisions the system being used first for high risk patients and eventually as a next generation, powerful cancer screening tool for the general population.
Another technique that is truly making waves at Stanford University is also based on detecting biomarkers at an early stage, but through a slightly different mechanism. It is well known in the scientific community that low frequency ultrasound energy perturbs the cellular outer membrane, permitting larger amounts of biomarkers to be spilled into the bloodstream. Multiple other research groups have exploited this phenomenon to increase the delivery of macromolecules into the cell. However, the Stanford team took a different approach to this concept and hypothesized that ultrasonic energy could also be used to facilitate the release of macromolecules from the cell itself. Specifically, their model focused on colon cancer and the release of Carcinoembryonic Antigen (CEA), a common biomarker in both colon and breast cancers. Since higher intensities of ultrasonic energy can kill the cells outright, Gambhir’s team spent a large chunk of time optimizing their protocols to ensure that they could stress cells – but not kill them – in both in vitro and in vivo experimental systems. To quote Dr. Gambhir, “The scientists yell and scare the tumours into revealing themselves.” Looking forward, the group envisions that individuals with known family histories or genetic predispositions to cancers in susceptible areas (such as the breasts and pelvis) would be the best candidates for this approach. In the clinic, the team plans on measuring biomarker levels in these high-risk patients before and after ultrasound to see if there is a corresponding increase in blood biomarkers.
…[T]he main obstacle to eliminating cancer is not our current treatments, but the fact that we are catching the disease far too late.”
In the eyes of the Canary Center for Cancer Early Detection, the main obstacle to eliminating cancer is not our current treatments, but the fact that we are catching the disease far too late. For Dr. Sanjiv Gambhir, this passion for early cancer detection is also a personal one. In 2015, his 16-year-old son Milan passed away after a 21-month battle with a very aggressive glioblastoma multiforme, one of the cancers Gambhir investigates in his own lab. By the time the tumour had been detected the cancer had already spread, making the chances of beating it very small. However, Milan Gambhir’s legacy lives on in his family, friends and in the scientific community. Not only are his cells being used in labs around the world that focus on pediatric high grade gliomas, but days after his death a Wearable Ultrasonic Device for the Early Detection of Tumour Recurrence that Milan had helped developed during his summer job at the Canary Center was patented. As for Dr. Sanjiv Gambhir, his frustrations and anger with the current approach to cancer treatment is only amplified by what happened to his son. To quote Dr. Gambhir, “As a society, we’ve failed our patients – instead of tackling the real problem, which is prevention and early detection, we’ve focused all our energies on the tail end of the problem.” His fight to revolutionize the field of cancer diagnostics carries on and his work continues to have an indisputable impact in both cancer diagnostics and patient care.
- D’Souza AL et al. A strategy for blood biomarker amplification and localization using ultrasound. Proceedings of the National Academy of Sciences, 106(40):17152–17157 (2009).
- Gambhir S. Molecular Spies for Early Disease Detection. TEDxStanford (2012).
- Leighton E. Gambhir: We pay a price for shying away. Western News (2015).
- Lou, K.J. Good vibrations in cancer. Science-Business eXchange, 2(41):1-2 (2009).
- Pysz MA et al. Molecular imaging: current status and emerging strategies. Clinical Radiology, 65(7):500–516 (2010).
- Ronald JA et al. Detecting cancers through tumor-activatable minicircles that lead to a detectable blood biomarker. Proceedings of the National Academy of Sciences, 112(10):3068–3073 (2015).
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