precision oncology
New 3D Atlas of Colorectal Cancer Promises Improved Diagnosis, Treatment
Posted on by Lawrence Tabak, D.D.S., Ph.D.
This year, too many Americans will go to the doctor for tissue biopsies to find out if they have cancer. Highly trained pathologists will examine the biopsies under a microscope for unusual cells that show the telltale physical features of a suspected cancer. As informative as the pathology will be for considering the road ahead, it would be even more helpful if pathologists had the tools to look widely inside cells for the actual molecules giving rise to the tumor.
Working this “molecular information” into the pathology report would bring greater diagnostic precision, drilling down to the actual biology driving the growth of the tumor. It also would help doctors to match the right treatments to a patient’s tumor and not waste time on drugs that will be ineffective.
That’s why researchers have been busy building the needed tools and also mapping out molecular atlases of common cancers. These atlases, really a series of 3D spatial maps detailing various biological features within the tumor, keep getting better all the time. That includes the comprehensive atlas of colorectal cancer just published in the journal Cell [1].
This colorectal atlas comes from an NIH-supported team led by Sandro Santagata, Brigham and Women’s Hospital, Boston, and Peter Sorger, Harvard Medical School, Cambridge, MA, in collaboration with investigators at Vanderbilt University, Nashville, TN. The colorectal atlas joins their previously published high-definition map of melanoma [2], and both are part of the Human Tumor Atlas Network that’s supported by NIH’s National Cancer Institute.
What’s so interesting with the colorectal atlas is the team combined traditional pathology with a sophisticated technique for imaging single cells, enabling them to capture their fine molecular details in an unprecedented way.
They did it using a cutting-edge technique known as cyclic immunofluorescence, or CyCIF. In CyCIF, researchers use many rounds of highly detailed molecular imaging on each tissue sample to generate a rich collection of molecular-level data, cell by cell. Altogether, the researchers captured this fine-scale visual information for nearly 100 million cancer cells isolated from tumor samples representing 93 individuals diagnosed with colorectal cancer.
With this single-cell information in hand, they next created detailed 2D maps covering the length and breadth of large portions of the colorectal cancers under study. Finally, with the aid of first author Jia-Ren Lin, also at Harvard Medical School, and colleagues they stitched together their 2D maps to produce detailed 3D reconstructions showing the length, breadth, and height of the tumors.
This more detailed view of colorectal cancer has allowed the team to explore differences between normal and tumor tissues, as well as variations within an individual tumor. In fact, they’ve uncovered physical features that had never been discovered.
For instance, an individual tumor has regions populated with malignant cells, while other areas look less affected by the cancer. In between are transitional areas that correspond to molecular gradients of information. With this high-resolution map as their guide, researchers can now study what this all might mean for the diagnosis, treatment, and prognosis of colorectal cancer.
The atlas also shows that the presence of immune cells varies dramatically within a single tumor. That’s an important discovery because of its potential implications for immunotherapies, in which treatments aim to unleash the immune system in the fight against cancer.
The maps also provide new insights into tumor structure. For example, scientists had previously identified what they thought were 2D pools of a mucus-like substance called mucin with clusters of cancer cells suspended inside. However, the new 3D reconstruction make clear that these aren’t simple mucin pools. Rather, they are cross sections of larger intricate caverns of mucin interconnected by channels, into which cancer cells make finger-like projections.
The good news is the researchers already are helping to bring these methods into the cancer clinic. They also hope to train other scientists to build their own cancer atlases and grow the collection even more.
In the meantime, the team will refine its 3D tumor reconstructions by integrating new imaging technologies and even more data into their maps. It also will map many more colorectal cancer samples to capture the diversity of their basic biology. Also of note, having created atlases for melanoma and colorectal cancer, the team has plans to tackle breast and brain cancers next.
Let me close by saying, if you’re between the ages of 45 and 75, don’t forget to stay up to date on your colorectal cancer screenings. These tests are very good, and they could save your life.
References:
[1] Multiplexed 3D atlas of state transitions and immune interaction in colorectal cancer. Lin JR, Wang S, Coy S, Chen YA, Yapp C, Tyler M, Nariya MK, Heiser CN, Lau KS, Santagata S, Sorger PK. Cell. 2023 Jan 19;186(2):363-381.e19.
[2] The spatial landscape of progression and immunoediting in primary melanoma at single-cell resolution. Nirmal AJ, Maliga Z, Vallius T, Quattrochi B, Chen AA, Jacobson CA, Pelletier RJ, Yapp C, Arias-Camison R, Chen YA, Lian CG, Murphy GF, Santagata S, Sorger PK. Cancer Discov. 2022 Jun 2;12(6):1518-1541.
Links:
Colorectal Cancer (National Cancer Institute/NIH)
Human Tumor Atlas Network (NCI)
CyCIF-Cyclic Immunofluorescence (Harvard Medical School, Cambridge, MA)
Sandro Santagata (Brigham and Women’s Hospital, Boston)
Peter Sorger (Harvard Medical School)
Jia-Ren Lin (Harvard Medical School)
NIH Support: National Cancer Institute; National Institute of General Medical Sciences; National Institute of Diabetes and Digestive and Kidney Diseases
A Global Look at Cancer Genomes
Posted on by Dr. Francis Collins
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)
The Cancer Genome Atlas Program (NIH)
NCI and the Precision Medicine Initiative (NCI)
NIH Support: National Cancer Institute, National Human Genome Research Institute
Personalized Combination Therapies Yield Better Cancer Outcomes
Posted on by Dr. Francis Collins
Gratifying progress has been made recently in an emerging area of cancer medicine called precision oncology. It’s a bold attempt to target treatment to the very genes and molecules driving a cancer, aiming to slow or even halt its growth. But there’s always more to learn. Now comes evidence that, while a single well-matched drug might be good, a tailored combination of drugs that attack a cancer in multiple ways at once might be even better.
The findings come from the I-PREDICT clinical trial, which treated people with advanced cancer who hadn’t benefited from previous therapy [1]. The NIH-funded team found that analyzing a tumor’s unique genetic and molecular profile provided enough information to recommend individualized combination therapies to patients. What’s more, patients who followed their individualized combination therapies most closely lived longer, with longer periods of progression-free disease, than did those who took fewer of the recommended drugs.
In most previous clinical trials of precision oncology, researchers have relied on a tumor’s unique profile to identify a single, well-matched drug to treat each patient. But cancer is complex, and, just as with certain infectious diseases, tumors commonly develop resistance to a single drug.
In the trial reported in Nature Medicine, researchers led by Razelle Kurzrock and Jason Sicklick, University of California, San Diego, wondered if they could improve treatment responses by tailoring combinations of cancer drugs to target as many molecular and genetic changes in a person’s cancer as possible.
To test the potential for this strategy to work, the researchers enrolled 83 people with various cancers that had advanced despite previous treatment. Tumor tissue from each patient was run through a comprehensive battery of tests, and researchers sequenced hundreds of genes to look for telltale alterations in their DNA.
They also looked for evidence that a cancer had defects affecting the DNA “mismatch repair” pathway, which causes some tumors to generate larger numbers of mutations than others. Mismatch repair defects have been shown to predict better responses to immunotherapies, which are designed to harness the immune system against cancer .
With all the data in hand, a special panel of oncologists, pharmacologists, cancer biologists, geneticists, surgeons, radiologists, pathologists, and bioinformatics experts consulted to arrive at the right customized combination of drugs for each patient.
The panel’s findings were presented to the health care team working with each patient. The physician for each patient then had the final decision on whether to recommend the treatment regimen, balancing the panel’s suggestions with other real-world factors, such as a patient’s insurance coverage, availability of drugs, and his or her treatment preference.
Ten patients decided to stick with unmatched treatment. But 73 participants received a customized combination therapy. As no two molecular profiles were identical, the customized treatment regimens varied from person to person.
Many people received designer drugs targeting particular genetic alterations. Some also received checkpoint inhibitor immunotherapies to unleash the immune system against cancer. Four people also were treated with hormone therapies in combination with molecularly targeted drugs. In all, most regimens combined two to five drugs to target each cancer profile.
Participants were followed until their cancer progressed, they could no longer take treatment, or they died. For each person, the researchers calculated a “matching score,” roughly defined as the number of molecular alterations matched to administered drug(s), with some further calculations.
The evidence showed that those with matching scores greater than 50 percent, meaning more than half of a tumor’s identified aberrations had been targeted, were more likely to have stopped the progression of their cancers. Importantly, half of patients with the higher matching scores had prolonged stable disease (six months or longer) or a complete or partial remission. Similar results were attained in only 22 percent of those with low or no matching scores.
These encouraging results suggest that customized combinations of targeted treatments will help to advance precision oncology. However, there are still many challenges. For example, many of the combinations used in the study have not yet been safety tested. The researchers managed the potential risk of toxicities by starting patients on an initial low dose and having their physicians follow them closely while the dose was increased to a level well-tolerated by each individual patient.
And indeed, they saw no evidence that those receiving a greater proportion of “matched” drugs (i.e. those with a higher matching score) were more likely to experience adverse effects than those who took fewer drugs. So, that’s an encouraging sign.
The researchers are now enrolling patients in a new version of the I-PREDICT trial. Unlike the initial plan, patients are now being enrolled prior to receiving any treatment for a recently diagnosed aggressive, often-lethal form of cancer. The hope is that treating patients with well-matched, multi-drug treatment combinations early will yield even better results than waiting until standard treatment has failed. If correct, it would mark significant progress in building the future of precision oncology.
Reference:
[1] Molecular profiling of cancer patients enables personalized combination therapy: the I-PREDICT study. Sicklick JK, Kato S, Okamura R, Schwaederle M, Hahn ME, Williams CB, De P, Krie A, Piccioni DE, Miller VA, Ross JS, Benson A, Webster J, Stephens PJ, Lee JJ, Fanta PT, Lippman SM, Leyland-Jones B, Kurzrock R. Nat Med. 2019 Apr 22.
Links:
Precision Medicine in Cancer Treatment (National Cancer Institute/NIH)
Study of Molecular Profile-Related Evidence to Determine Individualized Therapy for Advanced or Poor Prognosis Cancers (I-PREDICT) (Clinicaltrials.gov)
Razelle Kurzrock (University of California, San Diego)
Jason Sicklick (University of California, San Diego)
NIH Support: National Cancer Institute
Fighting Cancer with Natural Killer Cells
Posted on by Dr. Francis Collins
Credit: Michele Ardolino, University of Ottawa, and Brian Weist, Gilead Sciences, Foster City, CA
Cancer immunotherapies, which enlist a patient’s own immune system to attack and shrink developing tumors, have come a long way in recent years, leading in some instances to dramatic cures of widely disseminated cancers. But, as this video highlights, new insights from immunology are still being revealed that may provide even greater therapeutic potential.
Our immune system comes equipped with all kinds of specialized cells, including the infection-controlling Natural Killer (NK) cells. The video shows an army of NK cells (green) attacking a tumor in a mouse (blood vessels, blue) treated with a well-established type of cancer immunotherapy known as a checkpoint inhibitor. What makes the video so interesting is that researchers didn’t think checkpoint inhibitors could activate NK cells.
Working Toward Greater Precision in Childhood Cancers
Posted on by Dr. Francis Collins
Credit: National Cancer Institute, NIH
Each year, more than 15,000 American children and teenagers will be diagnosed with cancer. While great progress has been made in treating many types of childhood cancer, it remains the leading cause of disease-related death among kids who make it past infancy in the United States [1]. One reason for that sobering reality is our relatively limited knowledge about the precise biological mechanisms responsible for childhood cancers—information vital for designing targeted therapies to fight the disease in all its varied forms.
Now, two complementary studies have brought into clearer focus the genomic landscapes of many types of childhood cancer [2, 3]. The studies, which analyzed DNA data representing tumor and normal tissue from more than 2,600 young people with cancer, uncovered thousands of genomic alterations in about 200 different genes that appear to drive childhood cancers. These so-called “driver genes” included many that were different than those found in similar studies of adult cancers, as well as a considerable number of mutations that appear amenable to targeting with precision therapies already available or under development.
KRAS Targeted Cancer Strategy Shows Early Promise
Posted on by Dr. Francis Collins
Caption: Mutant KRAS protein (white) keeps switch (red/pink) open in active state for GTP (arrow). After treatment with ARS-1620 (blue), switch is trapped in inactive GDP-bound state.
Credit: Adapted from Cell. 2018 Jan 25;172(3):578-589.
Of the more than 1.7 million Americans expected to be diagnosed with cancer this year, nearly one-third will have tumors that contain at least one mutation in the RAS family of genes [1]. That includes 95 percent of pancreatic cancers and 45 percent of colon cancers. These mutations result in the production of defective proteins that can drive cancer’s uncontrolled growth, as well as make cancers resistant to therapies. As you might expect, RAS has emerged as a major potential target for fighting cancer. Unfortunately, it is a target that’s proven very difficult to “hit” despite nearly three decades of work by researchers in both the private and public sectors, leading NIH’s National Cancer Institute to begin The RAS Initiative in 2013. This important effort has made advances with RAS that have translational potential.
Recently, I was excited to hear of progress in targeting a specific mutant form of KRAS, which is a protein encoded by a RAS gene involved in many lung cancers and some pancreatic and colorectal cancers. The new study, carried out by a pharmaceutical research team in mouse models of human cancer, is the first to show that it is possible to shrink a tumor in a living creature by directly inhibiting mutant KRAS protein [2].
Precision Oncology: Gene Changes Predict Immunotherapy Response
Posted on by Dr. Francis Collins
Caption: Adapted from scanning electron micrograph of cytotoxic T cells (red) attacking a cancer cell (white).
Credits: Rita Elena Serda, Baylor College of Medicine; Jill George, NIH
There’s been tremendous excitement in the cancer community recently about the life-saving potential of immunotherapy. In this treatment strategy, a patient’s own immune system is enlisted to control and, in some cases, even cure the cancer. But despite many dramatic stories of response, immunotherapy doesn’t work for everyone. A major challenge has been figuring out how to identify with greater precision which patients are most likely to benefit from this new approach, and how to use that information to develop strategies to expand immunotherapy’s potential.
A couple of years ago, I wrote about early progress on this front, highlighting a small study in which NIH-funded researchers were able to predict which people with colorectal and other types of cancer would benefit from an immunotherapy drug called pembrolizumab (Keytruda®). The key seemed to be that tumors with defects affecting the “mismatch repair” pathway were more likely to benefit. Mismatch repair is involved in fixing small glitches that occur when DNA is copied during cell division. If a tumor is deficient in mismatch repair, it contains many more DNA mutations than other tumors—and, as it turns out, immunotherapy appears to be most effective against tumors with many mutations.
Now, I’m pleased to report more promising news from that clinical trial of pembrolizumab, which was expanded to include 86 adults with 12 different types of mismatch repair-deficient cancers that had been previously treated with at least one type of standard therapy [1]. After a year of biweekly infusions, more than half of the patients had their tumors shrink by at least 30 percent—and, even better, 18 had their tumors completely disappear!
Precision Oncology: Epigenetic Patterns Predict Glioblastoma Outcomes
Posted on by Dr. Francis Collins
Caption: Oncologists review a close-up image of a brain tumor (green dot).
Credit: National Cancer Institute
Scientists have spent much time and energy mapping the many DNA misspellings that can transform healthy cells into cancerous ones. But recently it has become increasingly clear that changes to the DNA sequence itself are not the only culprits. Cancer can also be driven by epigenetic changes to DNA—modifications to chemical marks on the genome don’t alter the sequence of the DNA molecule, but act to influence gene activity. A prime example of this can been seen in glioblastoma, a rare and deadly form of brain cancer that strikes about 12,000 Americans each year.
In fact, an NIH-funded research team recently published in Nature Communications the most complete portrait to date of the epigenetic patterns characteristic of the glioblastoma genome [1]. Among their findings were patterns associated with how long patients survived after the cancer was detected. While far more research is needed, the findings highlight the potential of epigenetic information to help doctors devise more precise ways of diagnosing, treating, and perhaps even preventing glioblastoma and many other forms of cancer.
Precision Oncology: Nanoparticles Target Bone Cancers in Dogs
Posted on by Dr. Francis Collins
Credit: L. Brian Stauffer
Many people share their homes with their pet dogs. Spending years under the same roof with the same environmental exposures, people and dogs have something else in common that sometimes gets overlooked. They can share some of the same diseases, such as diabetes and cancer. By studying these diseases in dogs, researchers can learn not only to improve care for people but for their canine friends as well.
As a case in point, an NIH-funded team of researchers recently tested a new method of delivering chemotherapy drugs for osteosarcoma, a bone cancer that affects dogs and people, typically teenagers and older adults. Their studies in dogs undergoing treatment for osteosarcoma suggest that specially engineered, bone-seeking nanoparticles might safely deliver anti-cancer drugs precisely to the places where they are most needed. These early findings come as encouraging news for the targeted treatment of inoperable bone cancers and other malignancies that spread to bone.
Study Shows DNA Sequencing Brings Greater Precision to Childhood Cancer
Posted on by Dr. Francis Collins
Caption: Baylor’s Sharon Plon consults with a family at the Texas Children’s Cancer Center in Houston.
Credit: Paul V. Kuntz/Texas Children’s Hospital
An impressive number of fundamental advances in our understanding of cancer have occurred over the past several decades. One of the most profound is the realization that cancer is a disease of the genome, driven by a wide array of changes in DNA—some in the germline and affecting all cells of the body, but most occurring in individual cells during life (so-called “somatic mutations”). As the technology for sequencing cancer genomes has advanced, we are learning that virtually all cancers carry a unique set of mutations. Most are DNA copying errors of no significance (we call those “passengers”), but a few of them occur in genes that regulate cell growth and contribute causatively to the cancer (we call those “drivers”). We are now learning that it may be far more important for treating cancer to figure out what driver mutations are present in a patient’s tumor than to identify in which organ it arose. And, as a new study shows, this approach even appears to have potential to help cancer’s littlest victims.
Using genomic technology to analyze both tumor and blood samples from a large number of children who’d been newly diagnosed with cancer, an NIH-funded research team uncovered genetic clues with the potential to refine diagnosis, identify inherited cancer susceptibility, or guide treatment for nearly 40 percent of the children [1]. The potential driver mutations spanned a broad spectrum of genes previously implicated not only in pediatric cancers, but also in adult cancers. While much more work remains to determine how genomic analyses can be used to devise precise, new strategies for treating kids with cancer, the study provides an excellent example of the kind of research that NIH hopes to accelerate under the nation’s new cancer “moonshot,” a research initiative recently announced by the President and being led by the Vice President.
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