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precision oncology

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


Personalized Combination Therapies Yield Better Cancer Outcomes

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Doctor consulting with patient
Credit: NIH National Cancer Institute Visuals Online/Daniel Sone

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

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GIF of immune cells attacking

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

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Pediatric Cancer

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

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KRAS in active and inactive states

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].


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