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colorectal cancer

Are Some Tumors Just ‘Born to Be Bad’?

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Human Colon Cancer Cells

Caption: Human colon cancer cells.
Credit: National Cancer Institute, NIH

Thanks to improvements in screening technologies and public health outreach, more cancers are being detected early. While that’s life-saving news for many people, it does raise some important questions about the management of small, early-stage tumors. Do some tumors take a long time to smolder in their original location before they spread, or metastasize, while others track to new, distant, and dangerous sites early in their course? Or, as the authors of a new NIH-funded study put it, are certain tumors just “born to be bad”?

To get some answers, these researchers recently used genomic data from 19 human colorectal tumors (malignant and benign) to model tumor development over time [1]. Their computer simulations showed that malignant tumors displayed distinctive spatial patterns of genetic mutations associated with early cell mobility. Cell mobility is a prerequisite for malignancy, and it indicates an elevated risk of tumors invading the surrounding tissue and spreading to other parts of the body. What’s more, the team’s experimental work uncovered evidence of early abnormal cell movement in more than half of the invasive tumors.

Much more remains to be done to validate these findings and extend them to other types of cancer. But the study suggests that spatial mutation patterns may someday prove useful in helping decide whether to pursue aggressive treatment for early-stage cancer or opt for careful monitoring instead.

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].

New ‘Liquid Biopsy’ Shows Early Promise in Detecting Cancer

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Liquid Biopsy Schematic

Caption: Liquid biopsy. Tumor cells shed protein and DNA into bloodstream for laboratory analysis and early cancer detection.

Early detection usually offers the best chance to beat cancer. Unfortunately, many tumors aren’t caught until they’ve grown relatively large and spread to other parts of the body. That’s why researchers have worked so tirelessly to develop new and more effective ways of screening for cancer as early as possible. One innovative approach, called “liquid biopsy,” screens for specific molecules that tumors release into the bloodstream.

Recently, an NIH-funded research team reported some encouraging results using a “universal” liquid biopsy called CancerSEEK [1]. By analyzing samples of a person’s blood for eight proteins and segments of 16 genes, CancerSEEK was able to detect most cases of eight different kinds of cancer, including some highly lethal forms—such as pancreatic, ovarian, and liver—that currently lack screening tests.

In a study of 1,005 people known to have one of eight early-stage tumor types, CancerSEEK detected the cancer in blood about 70 percent of the time, which is among the best performances to date for a blood test. Importantly, when CancerSEEK was performed on 812 healthy people without cancer, the test rarely delivered a false-positive result. The test can also be run relatively cheaply, at an estimated cost of less than $500.

Creative Minds: Using Machine Learning to Understand Genome Function

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Anshul Kundaje

Anshul Kundaje / Credit: Nalini Kartha

Science has always fascinated Anshul Kundaje, whether it was biology, physics, or chemistry. When he left his home country of India to pursue graduate studies in electrical engineering at Columbia University, New York, his plan was to focus on telecommunications and computer networks. But a course in computational genomics during his first semester showed him he could follow his interest in computing without giving up his love for biology.

Now an assistant professor of genetics and computer science at Stanford University, Palo Alto, CA, Kundaje has received a 2016 NIH Director’s New Innovator Award to explore not just how the human genome sequence encodes function, but also why it functions in the way that it does. Kundaje even envisions a time when it might be possible to use sophisticated computational approaches to predict the genomic basis of many human diseases.

A Surprising Match: Cancer Immunotherapy and Mismatch Repair

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Anti-PD-1 Immunotherapy

How Anti-PD-1 Immunotherapy Works. Before immunotherapy (top), the tumor cell’s PD-1 ligand, or PD-L1, molecule (red) binds to a type of white blood cell called a T-cell in a way that enables the tumor cell to evade destruction by the immune system. During immunotherapy (bottom), an anti-PD-1 inhibitor drug (bright green) blocks PD-L1 binding, enabling the T cell to target the tumor cell for destruction.
Credit: NIH

Mismatch repair genes have long been a source of fascination to basic biologists. Normally, these genes serve to fix the small glitches that occur when DNA is copied as cells divide. Most of the original work was done in bacteria, with no expectation of medical relevance. But, as often happens, basic science studies can provide a profoundly important foundation for advances in human health. The relevance of mismatch repair to cancer was dramatically revealed in 1993, when teams led by Bert Vogelstein of Johns Hopkins University School of Medicine, Baltimore, and Richard Kolodner, then of Harvard Medical School, Boston, discovered that mutations in human mismatch repair genes play a key role in the development of certain forms of colorectal cancer [1, 2].

That discovery has led to the ability to identify individuals who have inherited misspellings in these mismatch repair genes and are at high risk for colorectal cancer, providing an opportunity to personalize screening by starting colonoscopy at a very early age and, thereby, saving many lives. But now a new consequence of this work has appeared. Vogelstein and his colleagues report that mismatch repair research may help fight cancer in a way that few would have foreseen two decades ago: predicting which cancer patients are most likely to respond to a new class of immunotherapy drugs, called anti-programmed death 1 (PD-1) inhibitors.

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