Cancer remains a significant global health challenge, responsible for a substantial number of deaths worldwide. In 2016 alone, there were approximately 14.1 million new cases of cancer and 8.9 million cancer-related deaths. This accounted for about 13% of annual mortality, ranking second only to heart disease. Interestingly, the burden of cancer has shifted towards less developed countries, which now bear 57% of the total cancer cases and 65% of cancer-related deaths globally.
Lung cancer stands out as the primary cause of cancer-related deaths among males in both more and less developed countries. In more developed nations, it has even surpassed breast cancer as the leading cause of cancer death among females. However, breast cancer remains the predominant cause of cancer-related deaths among females in less developed countries. Additionally, colorectal cancer ranks high among both males and females in more developed countries, while prostate cancer is prevalent among males. In contrast, less developed countries face significant challenges with liver and stomach cancer among males and cervical cancer among females, contributing significantly to cancer mortality rates.
A substantial portion of cancer cases and deaths could be prevented by broadly applying effective prevention measures, such as tobacco control, vaccination, and the use of early detection tests. It is clear that development of a sensitive and specific technology to detect cancer at the earliest time possible could dramatically improve clinical outcomes.
We set out to develop a novel platform to enable earlier cancer detection when the patient’s tumor burden would be undetectable using conventional technologies, offering the potential for cure through surgical removal.
Screening for Cancer
Cancer screening involves using tests to detect cancer at an early stage or prevent its complications. Occasionally, screening tests are used for primary prevention, aiming to prevent cancer altogether, such as the Pap test for detecting precancerous changes in cervical cells before cancer develops. Surveillance is another aspect of screening, focused on monitoring for cancer recurrence.
Effective cancer screening relies on certain conditions. The cancer being screened for should be a significant cause of illness and death. There must be a reliable, safe, and acceptable test available for detecting early-stage disease. Understanding the natural progression of the cancer is crucial, along with its identifiable early asymptomatic stage. It’s important that, without intervention, most cases in a preclinical phase progress to a clinical phase. Accessible and effective treatment options must also be in place. Lastly, the screening test should be economically viable relative to overall medical care expenses.
Challenges arise when screening patients with undiagnosed cancer. Often, those who volunteer for screening are healthier, which can skew the results. Sometimes, screening merely accelerates the cancer diagnosis without altering the outcome. Slower-growing cancers are more easily detected through screening, leading to better outcomes because they tend to have a better prognosis. However, screening can also lead to overdiagnosis by detecting conditions that may never progress to harmful cancers.
When assessing the usefulness of a screening test, accuracy is paramount. Sensitivity measures a test’s ability to correctly identify those with cancer among the population with cancer, while specificity gauges its ability to accurately identify those without cancer among the population without cancer. It’s essential to note that no screening test can achieve 100% sensitivity and specificity, highlighting the need for ongoing evaluation and improvement of screening methods.
Current Screening Approaches
Current cancer screening methods primarily rely on traditional laboratory-based tests, which have their limitations. For instance, stool samples are often tested for blood presence, but these tests exhibit low sensitivity and specificity. Despite their drawbacks, they are still used due to their affordability. PSA screening for prostate cancer is another common approach, but it’s contentious due to the occurrence of false positive results.
Recently, newer technologies have emerged, offering potential advancements in early cancer detection. Of particular interest are blood tests capable of simultaneously screening for various primary cancers, including those lacking early detection methods. These tests aim to complement existing organ-specific screening methods. One promising approach is the “blood biopsy,” which involves detecting cancer-specific circulating tumor DNA (ctDNA) or circulating tumor cells (CTCs) in the bloodstream.
However, these newer screening methods come with their own set of challenges. Cost and turnaround time are significant concerns, and several obstacles must be addressed before blood-based screening tests, incorporating either CTCs or ctDNA, can become valuable tools for early cancer diagnosis.
Using CTCs in cancer management offers advantages such as isolating tumor cells for morphological and molecular analysis. In contrast, ctDNA analysis is currently limited to mutation detection. Despite their potential, using CTCs for early detection has limitations, including the variability in cancer cell release into circulation and the difficulty in identifying circulating cancer stem cells.
Although a correlation between tumor load and ctDNA has been established in many malignancies, patients with very early cancer may not shed detectable amounts of ctDNA with current technologies. Our understanding of ctDNA biology is still incomplete, necessitating further research to implement it effectively as a clinical cancer biomarker.
Overall, there is an urgent need for sensitive and specific early cancer detection methods to diagnose cancer early, monitor recurrence, identify residual cancer after treatment, and address the development of treatment resistance.
Graphene-Sensor Based Cancer Detection
In recent years, chip-based technologies capable of analyzing cancer-related plasma proteins have been developed to exploit the potential of more sensitive protein detection platforms. These sensors provide an analytical capability that is thousands of times more sensitive than conventional serum protein assays. One novel platform utilizes graphene as the capture surface.
Graphene is a 2D material that has a honeycomb-like structure consisting of single sp2 carbon layers. It’s uniquely low resistance to current flow makes it an ideal material for a biosensor. When proteins of interest are captured on the graphene surface in the presence of a current flow, electrodes underneath the graphene detect a current flux associated with the binding events. The degree of change in the current is directly related to the amount of material binding to the sensor surface.
Cancer-Specific Proteins Produced by All Solid Tumors During Angiogenesis
Cancer screening depends on the identification of cancer-related biomarkers that are specifically related to cancer cells and that are present in the earliest stages of cancer development. A hallmark of cancer is uncontrolled growth. Cancer cells proliferate in the tissues from which they arise, and they depend on the intrinsic blood supply in those tissues for nutrients and oxygen. When they reach a critical number of cells, they can no longer sustain their survival based on the pre-existing blood vessels. As few as 300 cells may lead to increased consumption of oxygen and nutrients that is beyond the capacity of the normal vascular supply to deliver.
Angiogenesis
When the cancer cell’s demand for oxygen exceeds their supply, they activate the emergency system all cells of the body possess, Hypoxia inducible factor (HIF). The HIF protein, normally destroyed within 2 minutes of its synthesis, is stabilized inside the cancer cells and can then act on the cellular DNA to upregulate survival genes. HIF turns on a cascade of signals that promote the sprouting of new blood vessels from the surrounding vasculature. The surrounding vessels are normally dormant, but in response to the HIF-driven signals they grow a vast network of new blood vessels to bring in oxygen and nutrients that enable the cancer cell population to thrive and spread to other sites in the body. This process is termed angiogenesis. It is a universal program in cancer. As such, the signaling molecules used in angiogenesis can be used to identify the presence of cancer in its early stages, long before it could be detected by conventional imaging technology.
Angiogenesis Biomarkers for Cancer Detection using the Graphene Sensor?
HIF upregulates a variety of biomarkers that have been found to be elevated in cancer patient serum compared to normal controls. Several clinical studies demonstrated that these HIF-related markers are higher in cancer patient serum than in normal patients. HIF serum levels were found to be significantly higher in cancer than in normal controls. Similarly, Carbonic Anhydrase IX, a key enzyme upregulated by HIF to maintain normal pH, has also been found to be elevated in cancer patients and proportionate to their disease burden.
Taken together, these data show that angiogenic biomarkers can provide a means of detecting the presence of early cancer independent of cancer type. These markers are elaborated by cancer cells into the blood when their numbers reach only hundreds to thousands. Using exquisitely sensitive graphene-based sensors for their detection provides a path forward to early cancer detection. Validation studies are ongoing to confirm the utility of this approach.
