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Tackling Cancer Metastasis with Engineered Blood Platelets

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Tara Deans
Credit: Dan Hixson/University of Utah College of Engineering, Salt Lake City

When cancer cells spread to new parts of the body in a process called metastasis, they often get there by traveling through the bloodstream. To avoid alerting the immune system and possibly triggering their demise, cancer cells coax circulating blood platelets to glom onto their surfaces and mask them from detection. This deceptive arrangement has raised a tantalizing possibility: What if blood platelets could be programmed to recognize and take out those metastasizing cancer cells?

Tara Deans, University of Utah, Salt Lake City, was recently awarded a 2019 NIH Director’s New Innovator Award to do exactly that. It’s an exciting opportunity for a researcher who stumbled onto this innovative strategy quite by accident.

Deans is a bioengineer and expert in designing synthetic gene circuits. These circuits consist of small collections of genetic “parts” that can be assembled and integrated to program cells to behave differently than their natural counterparts [1]. In her initial work, Deans got these specialized gene circuits to prompt blood-forming stem cells to mass-produce platelets in the lab.

But blood platelets are unusual cells. They’re packed with many proteins that help to repair small nicks in blood vessels and stop the bleeding when we’re injured. Blood platelets do so even though they lack a nucleus and DNA to encode and make any of the proteins. Their protein cargo is pre-packaged and comes strictly from the bone marrow cells, called megakaryocytes, that produce them.

Deans realized that engineering platelets might pose a rare opportunity. She could wire the needed circuitry into the blood-forming stem cells and engineer them to make any desired therapeutic proteins, which are then loaded into the blood platelets for their 8- to 10-day lifespan. She started out producing blood platelets that could safely carry functional replacement enzymes in people with certain rare metabolic disorders.

As this research progressed, Deans got some troubling personal news: A friend was diagnosed with a blood cancer. At the time, Deans didn’t know much about the diagnosis. But, in reading about her friend’s cancer, she learned how metastasizing tumor cells interact with platelets.

That’s when Deans had her “aha” moment: maybe the engineered platelets could also be put to work in preventing metastasizing tumor cells from spreading.

Now, with her New Innovator Award, Deans will pursue this novel approach by engineering platelets to carry potentially promising cancer-fighting proteins. In principle, they could be tailored to fight breast, lung, and various other cancer types. Ultimately, she hopes that platelets could be engineered to target and kill circulating cancer cells before they move into other tissues.

There’s plenty of research ahead to work out the details of targeting the circulating cancer cells and then testing them in animal models before this strategy could ever be attempted in people. But Deans is excited about the path forward, and thinks that platelets hold great promise to function as unique drug delivery devices. It has not escaped her notice that this approach could work not only for controlling the spread of cancer cells, but also in treating other medical conditions.

Reference:

[1] Genetic circuits to engineer tissues with alternative functions. Healy CP, Deans TL. J Biol Eng. 2019 May 3;13:39.

Links:

Metastatic Cancer (National Cancer Institute/NIH)

Deans Lab (University of Utah, Salt Lake City)

Deans Project Information (NIH RePORTER)

NIH Director’s New Innovator Award (Common Fund)

NIH Support: Common Fund; National Cancer Institute


See the Human Cardiovascular System in a Whole New Way

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Watch this brief video and you might guess you’re seeing an animated line drawing, gradually revealing a delicate take on a familiar system: the internal structures of the human body. But this movie doesn’t capture the work of a talented sketch artist. It was created using the first 3D, full-body imaging device using positron emission tomography (PET).

The device is called an EXPLORER (EXtreme Performance LOng axial REsearch scanneR) total-body PET scanner. By pairing this scanner with an advanced method for reconstructing images from vast quantities of data, the researchers can make movies.

For this movie in particular, the researchers injected small amounts of a short-lived radioactive tracer—an essential component of all PET scans—into the lower leg of a study volunteer. They then sat back as the scanner captured images of the tracer moving up the leg and into the body, where it enters the heart. The tracer moves through the heart’s right ventricle to the lungs, back through the left ventricle, and up to the brain. Keep watching, and, near the 30-second mark, you will see in closer focus a haunting capture of the beating heart.

This groundbreaking scanner was developed and tested by Jinyi Qi, Simon Cherry, Ramsey Badawi, and their colleagues at the University of California, Davis [1]. As the NIH-funded researchers reported recently in Proceedings of the National Academy of Sciences, their new scanner can capture dynamic changes in the body that take place in a tenth of a second [2]. That’s faster than the blink of an eye!

This movie is composed of frames captured at 0.1-second intervals. It highlights a feature that makes this scanner so unique: its ability to visualize the whole body at once. Other medical imaging methods, including MRI, CT, and traditional PET scans, can be used to capture beautiful images of the heart or the brain, for example. But they can’t show what’s happening in the heart and brain at the same time.

The ability to capture the dynamics of radioactive tracers in multiple organs at once opens a new window into human biology. For example, the EXPLORER system makes it possible to measure inflammation that occurs in many parts of the body after a heart attack, as well as to study interactions between the brain and gut in Parkinson’s disease and other disorders.

EXPLORER also offers other advantages. It’s extra sensitive, which enables it to capture images other scanners would miss—and with a lower dose of radiation. It’s also much faster than a regular PET scanner, making it especially useful for imaging wiggly kids. And it expands the realm of research possibilities for PET imaging studies. For instance, researchers might repeatedly image a person with arthritis over time to observe changes that may be related to treatments or exercise.

Currently, the UC Davis team is working with colleagues at the University of California, San Francisco to use EXPLORER to enhance our understanding of HIV infection. Their preliminary findings show that the scanner makes it easier to capture where the human immunodeficiency virus (HIV), the cause of AIDS, is lurking in the body by picking up on signals too weak to be seen on traditional PET scans.

While the research potential for this scanner is clearly vast, it also holds promise for clinical use. In fact, a commercial version of the scanner, called uEXPLORER, has been approved by the FDA and is in use at UC Davis [3]. The researchers have found that its improved sensitivity makes it much easier to detect cancers in patients who are obese and, therefore, harder to image well using traditional PET scanners.

As soon as the COVID-19 outbreak subsides enough to allow clinical research to resume, the researchers say they’ll begin recruiting patients with cancer into a clinical study designed to compare traditional PET and EXPLORER scans directly.

As these researchers, and other researchers around the world, begin to put this new scanner to use, we can look forward to seeing many more remarkable movies like this one. Imagine what they will reveal!

References:

[1] First human imaging studies with the EXPLORER total-body PET scanner. Badawi RD, Shi H, Hu P, Chen S, Xu T, Price PM, Ding Y, Spencer BA, Nardo L, Liu W, Bao J, Jones T, Li H, Cherry SR. J Nucl Med. 2019 Mar;60(3):299-303.

[2] Subsecond total-body imaging using ultrasensitive positron emission tomography. Zhang X, Cherry SR, Xie Z, Shi H, Badawi RD, Qi J. Proc Natl Acad Sci U S A. 2020 Feb 4;117(5):2265-2267.

[3] “United Imaging Healthcare uEXPLORER Total-body Scanner Cleared by FDA, Available in U.S. Early 2019.” Cision PR Newswire. January 22, 2019.

Links:

Positron Emission Tomography (PET) (NIH Clinical Center)

EXPLORER Total-Body PET Scanner (University of California, Davis)

Cherry Lab (UC Davis)

Badawi Lab (UC Davis Medical Center, Sacramento)

NIH Support: National Cancer Institute; National Institute of Biomedical Imaging and Bioengineering; Common Fund


Prostate Cancer: Combined Biopsy Strategy Makes for More Accurate Diagnosis

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Doctor consult
Credit: iStock

Last year, nearly 175,000 American men were diagnosed with prostate cancer [1]. Most got the bad news after a blood test or physical exam raised concerns that warranted a biopsy of the prostate, a walnut-sized gland just below the bladder.

Traditional biopsies sample tissue from 12 systematically placed points within the prostate that are blind to tumor locations. Such procedures have helped to save many lives, but are prone to missing or misclassifying prostate cancers, which has led doctors both to over and under treat their patients.

Now, there may be a better approach. In a study of more than 2,000 men, NIH researchers and their colleagues recently found that combining the 12-point biopsy with magnetic resonance imaging (MRI)-targeted biopsy during the same session more accurately diagnoses prostate cancer than either technique alone [2].

The findings address a long-standing challenge in prostate cancer diagnostics: performing a thorough prostate biopsy to allow a pathologist to characterize as accurately as possible the behavior of a tumor. Some prostate tumors are small, slow growing, and can be monitored closely without treatment. Other tumors are aggressive and can grow rapidly, requiring immediate intervention with hormonal therapy, radiation, or surgery.

But performing a thorough prostate biopsy can run into technical difficulties. The 12-point biopsy blindly samples tissue from across the prostate gland, but it can miss a cancer by not probing in the right places.

Several years ago, researchers at the NIH Clinical Center, Bethesda, MD, envisioned a solution. They’d use specially designed MRI images of a man’s prostate to guide the biopsy needle to areas in the prostate that look suspicious and deserve a closer look under a microscope.

Through a cooperative research-and-development agreement, NIH and the now- Florida-based Philips Healthcare created an office-based, outpatient prostate biopsy device, called UroNav, that was later approved by the Food and Drug Administration. The UroNav system relies on software that overlays MRI images highlighting suspicious areas onto real-time ultrasound images of the prostate that are traditionally used to guide biopsy procedures.

The new technology led to a large clinical study led by Peter Pinto, a researcher with NIH’s National Cancer Institute. The study results, published in 2015, found that the MRI-targeted approach was indeed superior to the 12-point biopsy at detecting aggressive prostate cancers [3].

But some doctors had questions about how best to implement the UroNav system and whether it could replace the 12-point biopsy. The uncertainty led to a second clinical study to nail down more answers, and the results were just published in The New England Journal of Medicine.

The research team enrolled 2,103 men who had visible prostate abnormalities on an MRI. Once in the study, each man underwent both the 12-point blind biopsy and the MRI-targeted approach—all in a single office visit. Based on this two-step approach, 1,312 people were diagnosed with prostate cancer. Of that total, 404 men had evidence of aggressive cancer, and had their prostates surgically removed.

The researchers then compared the diagnoses from each approach alone versus the two combined. The data showed that the combined biopsy found 208 cancers that the standard 12-point biopsy alone would have missed. Adding the MRI-targeted biopsy also helped doctors find and sample the more aggressive cancers. This allowed them to upgrade the diagnosis of 458 cancers to aggressive and in need of more full treatment.

Combining the two approaches also led to more accurate diagnoses. By carefully analyzing the 404 removed prostates and comparing them to the biopsy results, the researchers found the 12-point biopsy missed the most aggressive cancers about 40 percent of the time. But the MRI-targeted approach alone missed it about 30 percent of the time. Combined, they did much better, underestimating the severity of less than 15 percent of the cancers.

Even better, the combined biopsy missed only 3.5 percent of the most aggressive tumors. That’s compared to misses of about 17 percent for the most-aggressive cancers for the 12-point biopsy alone and about 9 percent for MRI-targeted biopsy alone.

It may take time for doctors to change how they detect prostate cancer in their practices. But the findings show that combining both approaches will significantly improve the accuracy of diagnosing prostate cancer. This will, in turn, help to reduce risk of suboptimal treatment (too much or too little) by allowing doctors and patients to feel more confident in the biopsy results. That should come as good news now and in the future for the families and friends of men who will need an accurate prostate biopsy to make informed treatment decisions.

References:

[1] Cancer State Facts: Prostate Cancer. National Cancer Institute Surveillance, Epidemiology, and End Results Program.

[2] MRI-targeted, systematic, and combined biopsy for prostate cancer diagnosis. Ahdoot M, Wilbur AR, Reese SE, Lebastchi AH, Mehralivand S, Gomella PT, Bloom J, Gurram S, Siddiqui M, Pinsky P, Parnes H, Linehan WM, Merino M, Choyke PL, Shih JH, Turkbey B, Wood BJ, Pinto PA. N Engl J Med. 2020 Mar 5;382(10):917-928.

[3] Comparison of MR/ultrasound fusion-guided biopsy with ultrasound-guided biopsy for the diagnosis of prostate cancer. Siddiqui M, Rais-Bahrami, George AK, Rothwax J, Shakir N, Okoro C, Raskolnikov D, Parnes HL, Linehan WM, Merino MJ, Simon RM, Choyke PL, Wood BJ, and Pinto PA. JAMA. 2015 January 27;313(4):390-397.

Links:

Prostate Cancer (National Cancer Institute/NIH)

Video: MRI-Targeted Prostate Biopsy (YouTube)

Pinto Lab (National Cancer Institute/NIH)

NIH Support: National Cancer Institute; NIH Clinical Center


A Global Look at Cancer Genomes

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Cancer Genomics

Cancer is a disease of the genome. It can be driven by many different types of DNA misspellings and rearrangements, which can cause cells to grow uncontrollably. While the first oncogenes with the potential to cause cancer were discovered more than 35 years ago, it’s been a long slog to catalog the universe of these potential DNA contributors to malignancy, let alone explore how they might inform diagnosis and treatment. So, I’m thrilled that an international team has completed the most comprehensive study to date of the entire genomes—the complete sets of DNA—of 38 different types of cancer.

Among the team’s most important discoveries is that the vast majority of tumors—about 95 percent—contained at least one identifiable spelling change in their genomes that appeared to drive the cancer [1]. That’s significantly higher than the level of “driver mutations” found in past studies that analyzed only a tumor’s exome, the small fraction of the genome that codes for proteins. Because many cancer drugs are designed to target specific proteins affected by driver mutations, the new findings indicate it may be worthwhile, perhaps even life-saving in many cases, to sequence the entire tumor genomes of a great many more people with cancer.

The latest findings, detailed in an impressive collection of 23 papers published in Nature and its affiliated journals, come from the international Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. Also known as the Pan-Cancer Project for short, it builds on earlier efforts to characterize the genomes of many cancer types, including NIH’s The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC).

In these latest studies, a team including more than 1,300 researchers from around the world analyzed the complete genomes of more than 2,600 cancer samples. Those samples included tumors of the brain, skin, esophagus, liver, and more, along with matched healthy cells taken from the same individuals.

In each of the resulting new studies, teams of researchers dug deep into various aspects of the cancer DNA findings to make a series of important inferences and discoveries. Here are a few intriguing highlights:

• The average cancer genome was found to contain not just one driver mutation, but four or five.

• About 13 percent of those driver mutations were found in so-called non-coding DNA, portions of the genome that don’t code for proteins [2].

• The mutations arose within about 100 different molecular processes, as indicated by their unique patterns or “mutational signatures.” [3,4].

• Some of those signatures are associated with known cancer causes, including aberrant DNA repair and exposure to known carcinogens, such as tobacco smoke or UV light. Interestingly, many others are as-yet unexplained, suggesting there’s more to learn with potentially important implications for cancer prevention and drug development.

• A comprehensive analysis of 47 million genetic changes pieced together the chronology of cancer-causing mutations. This work revealed that many driver mutations occur years, if not decades, prior to a cancer’s diagnosis, a discovery with potentially important implications for early cancer detection [5].

The findings represent a big step toward cataloging all the major cancer-causing mutations with important implications for the future of precision cancer care. And yet, the fact that the drivers in 5 percent of cancers continue to remain mysterious (though they do have RNA abnormalities) comes as a reminder that there’s still a lot more work to do. The challenging next steps include connecting the cancer genome data to treatments and building meaningful predictors of patient outcomes.

To help in these endeavors, the Pan-Cancer Project has made all of its data and analytic tools available to the research community. As researchers at NIH and around the world continue to detail the diverse genetic drivers of cancer and the molecular processes that contribute to them, there is hope that these findings and others will ultimately vanquish, or at least rein in, this Emperor of All Maladies.

References:

[1] Pan-Cancer analysis of whole genomes. ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium. Nature. 2020 Feb;578(7793):82-93.

[2] Analyses of non-coding somatic drivers in 2,658 cancer whole genomes. Rheinbay E et al; PCAWG Consortium. Nature. 2020 Feb;578(7793):102-111.

[3] The repertoire of mutational signatures in human cancer. Alexandrov LB et al; PCAWG Consortium. Nature. 2020 Feb;578(7793):94-101.

[4] Patterns of somatic structural variation in human cancer genomes. Li Y et al; PCAWG Consortium. Nature. 2020 Feb;578(7793):112-121.

[5] The evolutionary history of 2,658 cancers. Gerstung M, Jolly C, Leshchiner I, Dentro SC et al; PCAWG Consortium. Nature. 2020 Feb;578(7793):122-128.

Links:

The Genetics of Cancer (National Cancer Institute/NIH)

Precision Medicine in Cancer Treatment (NCI)

ICGC/TCGA Pan-Cancer Project

The Cancer Genome Atlas Program (NIH)

NCI and the Precision Medicine Initiative (NCI)

NIH Support: National Cancer Institute, National Human Genome Research Institute


Working to Improve Immunotherapy for Lung Cancer

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Lung Cancer Immunotherapy
Credit: Xiaodong Zhu, Fred Hutchinson Cancer Research Center, Seattle

For those who track cancer statistics, this year started off on a positive note with word that lung cancer deaths continue to decline in the United States [1]. While there’s plenty of credit to go around for that encouraging news—and continued reduction in smoking is a big factor—some of this progress likely can be ascribed to a type of immunotherapy, called PD-1 inhibitors. This revolutionary approach has dramatically changed the treatment landscape for the most common type of lung cancer, non-small cell lung cancer (NSCLC).

PD-1 inhibitors, which have only been available for about five years, prime one component of a patient’s own immune system, called T cells, to seek and destroy malignant cells in the lungs. Unfortunately, however, only about 20 percent of people with NSCLC respond to PD-1 inhibitors. So, many researchers, including the team of A. McGarry Houghton, Fred Hutchinson Cancer Research Center, Seattle, are working hard to extend the benefits of immunotherapy to more cancer patients.

The team’s latest paper, published in JCI Insight [2], reveals that one culprit behind a poor response to immunotherapy may be the immune system’s own first responders: neutrophils. Billions of neutrophils circulate throughout the body to track down abnormalities, such as harmful bacteria and malignant cells. They also contact other parts of the immune system, including T cells, if help is needed to eliminate the health threat.

In their study, the Houghton team, led by Julia Kargl, combined several lab techniques to take a rigorous, unbiased look at the immune cell profiles of tumor samples from dozens of NSCLC patients who received PD-1 inhibitors as a frontline treatment. The micrographs above show tumor samples from two of these patients.

In the image on the left, large swaths of T cells (light blue) have infiltrated the cancer cells (white specks). Interestingly, other immune cells, including neutrophils (magenta), are sparse.

In contrast, in the image on the right, T cells (light blue) are sparse. Instead, the tumor teems with other types of immune cells, including macrophages (red), two types of monocytes (yellow, green), and, most significantly, lots of neutrophils (magenta). These cells arise from myeloid progenitor cells in the bone marrow, while T cells arise from the marrow’s lymphoid progenitor cell.

Though the immune profiles of some tumor samples were tough to classify, the researchers found that most fit neatly into two subgroups: tumors showing active levels of T cell infiltration (like the image on the left) or those with large numbers of myeloid immune cells, especially neutrophils (like the image on the right). This dichotomy then served as a reliable predictor of treatment outcome. In the tumor samples with majority T cells, the PD-1 inhibitor worked to varying degrees. But in the tumor samples with predominantly neutrophil infiltration, the treatment failed.

Houghton’s team has previously found that many cancers, including NSCLC, actively recruit neutrophils, turning them into zombie-like helpers that falsely signal other immune cells, like T cells, to stay away. Based on this information, Houghton and colleagues used a mouse model of lung cancer to explore a possible way to increase the success rate of PD-1 immunotherapy.

In their mouse experiments, the researchers found that when PD-1 was combined with an existing drug that inhibits neutrophils, lung tumors infiltrated with neutrophils were converted into tumors infiltrated by T cells. The tumors treated with the combination treatment also expressed genes associated with an active immunotherapy response.

This year, January brought encouraging news about decreasing deaths from lung cancer. But with ongoing basic research, like this study, to tease out the mechanisms underlying the success and failure of immunotherapy, future months may bring even better news.

References:

[1] Cancer statistics, 2020. Siegel RL, Miller KD, Jemal A. CA Cancer J Clin. 2020 Jan;70(1):7-30.

[2] Neutrophil content predicts lymphocyte depletion and anti-PD1 treatment failure in NSCLC. Kargl J, Zhu X, Zhang H, Yang GHY, Friesen TJ, Shipley M, Maeda DY, Zebala JA, McKay-Fleisch J, Meredith G, Mashadi-Hossein A, Baik C, Pierce RH, Redman MW, Thompson JC, Albelda SM, Bolouri H, Houghton AM. JCI Insight. 2019 Dec 19;4(24).

[3] Neutrophils dominate the immune cell composition in non-small cell lung cancer. Kargl J, Busch SE, Yang GH, Kim KH, Hanke ML, Metz HE, Hubbard JJ, Lee SM, Madtes DK, McIntosh MW, Houghton AM. Nat Commun. 2017 Feb 1;8:14381.

Links:

Non-Small Cell Lung Cancer Treatment (PDQ®)–Patient Version (National Cancer Institute/NIH)

Spotlight on McGarry Houghton (Fred Hutchinson Cancer Research Center, Seattle)

Houghton Lab (Fred Hutchinson Cancer Research Center)

NIH Support: National Cancer Institute


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