Howard Hughes Medical Institute Investigator Sangeeta Bhatia and members of her lab at MIT are working to make early detection of lung cancer possible in regions of the world that lack access to advanced imaging technologies and diagnostic labs. 

Lung cancer is the leading cause of cancer-related deaths worldwide, but mortality rates are disproportionately highest in low- and middle-income countries. In the US, for example, lung cancer mortality rates have actually declined by four to five percent per year from 2015 to 2019, according to the US Annual Report to the Nation on the Status of Cancerexternal link, opens in a new tab. This decline is largely credited to early diagnosis and treatment spurred by advances in both screening technology and available therapies.

Unfortunately, resource-poor regions of the world often lack access to advanced screening technology; even in the US, barriers to patient access to early diagnostic care — as well as a scarcity of trained imaging personnel — can impact the timing of a patient’s diagnosis.   

Recognizing this challenge, researchers in Bhatia’s lab set out to develop a low-cost, point-of-care tool to detect lung cancer, even in its earliest stages. The group’s platform, known as “PATROL,” uses nanosensors that are designed to release engineered biomarkers for lung cancer into the bloodstream if the sensors encounter enzyme activity indicative of tumors. When this happens, the biomarkers make their way through the bloodstream and accumulate in the urine, where they can be detected without the use of imaging technologies or invasive screening procedures. 

PATROL’s technology is promising; thus far, in mouse models, the platform has proven effective in detecting early-stage tumors with high sensitivity and specificity.

“The beauty of this technology is how accessible it is,” says Qian Zhong, a research scientist in Bhatia’s lab who led PATROL’s design along with Edward Tan, a former MIT postdoc in the lab. In countries like the US, patients are typically screened for lung cancer via CT scan. “That requires patients to visit a medical center with imaging capabilities,” Zhong says. “But here, we’re talking about deploying technology to anywhere in the world without compromising accuracy.”

For more than a decade, Bhatia’s lab has demonstrated unique expertise in the area of research known as activity-based diagnostics. Bhatia and her team have developed techniques to decorate nanosensors with biological molecules commonly existing in human cells, such as DNA barcodes that could be used to signal the presence of disease. Upon delivery into the body, the nanosensors are designed to trigger the release of these DNA barcodes into the bloodstream if and when they encounter enzymes known as proteases, which are often overactive in cancer. After the barcode circulates through the bloodstream, it eventually concentrates in the bladder, allowing for detection via a simple urine-based test that’s a similar concept in design — and simplicity — to an at-home pregnancy test.

One of the biggest challenges in utilizing activity-based nanosensors that tap proteases as biomarkers for cancer is that cancer-associated proteases are typically local to the tumor microenvironment. If the nanosensors can’t reach these sites, the diagnostic test won’t present reliable results. 

Fortunately, the lungs offer a unique entry point by way of the respiratory system. Knowing this, Zhong and Tan created an inhalable version of the lab’s nanosensor technology to enable direct delivery to the lungs via a simple handheld inhaler or a nebulizer, such as those commonly used to treat asthma.

Because lung cancer is a complex disease, there are many biomarkers that could indicate its presence. As such, Zhong and Tan worked with other members of Bhatia’s lab to determine which protease substrates would be most useful in diagnosing lung cancer. “It’s essentially like we’re trying to fingerprint the tumor microenvironment,” Tan says. “It’s tough.” Together with Bhatia and other members of her lab, the duo designed PATROL to use four different DNA barcodes to detect a panel of proteases most likely to indicate lung cancer in preclinical mouse models. Even more, these proteases can be detected with a single test, and results can be read just 20 minutes after a urine sample is produced.  

“The incidence of lung cancer is increasing in low- and middle-income countries — driven in part by pollution and smoking,” Bhatia says. “We hope that an accessible diagnostic technology could improve access to screening and help intercept cancer when it is most treatable.”

The research team’s future plans include analyzing biopsy samples to see if the same “fingerprints” would recognize human cancer samples. Additionally, the researchers will explore how this technology could be used to detect other pulmonary diseases such as chronic obstructive pulmonary disease and asthma. Further, they plan to investigate if PATROL — or platforms like it — could be used to monitor cancer progression and treatment response, allowing clinicians to better predict how patients might respond to certain treatment strategies, such as immunotherapies.

The team’s work was first reported in a preprintexternal link, opens in a new tab and subsequently publishedexternal link, opens in a new tab on January 5, 2024.

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Citations

Preprint. "Inhalable point-of-care urinary diagnostic platformexternal link, opens in a new tab." Qian Zhong, Edward K.W. Tan, Carmen Martin-Alonso, Tiziana Parisi, Liangliang Hao, Jesse D. Kirkpatrick, Tarek Fadel, Heather E. Fleming, Tyler Jacks, Sangeeta N. Bhatia. doi: 10.1101/2023.09.30.560328

Zhong, Qian, et al. “Inhalable Point-of-Care Urinary Diagnostic Platformexternal link, opens in a new tab.” PMID: 38181080