Creative Minds: Applying CRISPR Technology to Cancer Drug Resistance

Patrick Hsu

Patrick Hsu

As a child, Patrick Hsu once settled a disagreement with his mother over antibacterial wipes by testing them in controlled experiments in the kitchen. When the family moved to Palo Alto, CA, instead of trying out for the football team or asking to borrow the family car like other high school kids might have done, Hsu went knocking on doors of scientists at Stanford University. He found his way into a neuroscience lab, where he gained experience with the fundamental tools of biology and a fascination for understanding how the brain works. But Hsu would soon become impatient with the tools that were available to ask some of the big questions he wanted to study.

As a Salk Helmsley Fellow and principal investigator at the Salk Institute for Biological Studies, La Jolla, CA, Hsu now works at the intersection of bioengineering, genomics, and neuroscience with a DNA editing tool called CRISPR/Cas9 that is revolutionizing the way scientists can ask and answer those big questions. (This blog has previously featured several examples of how this technology is revolutionizing biomedical research.) Hsu has received a 2015 NIH Director’s Early Independence award to adapt CRISPR/Cas9 technology so its use can be extended to that other critically important information-containing nucleic acid—RNA.Specifically, Hsu aims to develop ways to use this new tool to examine the role of a certain type of RNA in cancer drug resistance.

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Precision Oncology: Creating a Genomic Guide for Melanoma Therapy

Melanoma cell

Caption: Human malignant melanoma cell viewed through a fluorescent, laser-scanning confocal microscope. Invasive structures involved in metastasis appear as greenish-yellow dots, while actin (green) and vinculin (red) are components of the cell’s cytoskeleton.
Credit: Vira V. Artym, National Institute of Dental and Craniofacial Research, NIH

It’s still the case in most medical care systems that cancers are classified mainly by the type of tissue or part of the body in which they arose—lung, brain, breast, colon, pancreas, and so on. But a radical change is underway. Thanks to advances in scientific knowledge and DNA sequencing technology, researchers are identifying the molecular fingerprints of various cancers and using them to divide cancer’s once-broad categories into far more precise types and subtypes. They are also discovering that cancers that arise in totally different parts of the body can sometimes have a lot in common. Not only can molecular analysis refine diagnosis and provide new insights into what’s driving the growth of a specific tumor, it may also point to the treatment strategy with the greatest chance of helping a particular patient.

The latest cancer to undergo such rigorous, comprehensive molecular analysis is malignant melanoma. While melanoma can rarely arise in the eye and a few other parts of the body, this report focused on the more familiar “cutaneous melanoma,” a deadly and increasingly common form of skin cancer [1].  Reporting in the journal Cell [2], The Cancer Genome Atlas (TCGA) Network says it has identified four distinct molecular subtypes of melanoma. In addition, the NIH-funded network identified an immune signature that spans all four subtypes. Together, these achievements establish a much-needed framework that may guide decisions about which targeted drug, immunotherapy, or combination of therapies to try in an individual with melanoma.

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Knocking Out Melanoma: Does This Triple Combo Have What It Takes?

3-Way Knockout of MelanomaIt would be great if we could knock out cancer with a single punch. But the more we learn about cancer’s molecular complexities and the immune system’s response to tumors, the more it appears that we may need a precise combination of blows to defeat a patient’s cancer permanently, with no need for a later rematch. One cancer that provides us with a ringside seat on the powerful potential—and tough challenges—of targeted combination therapy is melanoma, especially the approximately 50% of advanced tumors with a specific “driver” mutation in the BRAF gene [1].

Drugs that target cells carrying BRAF mutations initially provided great hope for melanoma, with many reports of dramatic shrinkage of tumors in patients with advanced disease.  But almost invariably, the disease recurred and was no longer responsive to those same drugs.  A few years ago, researchers thought they’d come up with a solid combination to fight BRAF-mutant melanoma: a one-two punch that paired a BRAF-inhibiting drug with an agent that sensitized the immune system [2]. However, when that combo was tested in humans, the clinical trial had to be stopped early because of serious liver toxicity [3]. Now, in a mouse study published in Science Translational Medicine, NIH-funded researchers at the University of California, Los Angeles (UCLA) provide renewed hope for a safe, effective combination therapy for melanoma—with a strategy that adds a third drug to the mix [4].

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Snapshots of Life: Portrait of Skin Cancer

Squamous cell carcinoma

Caption: This image shows the uncontrolled growth of cells in squamous cell carcinoma.
Credit: Markus Schober and Elaine Fuchs, The Rockefeller University, New York

For Markus Schober, science is more inspiring when the images are beautiful, even when the subject is not. So, when this biologist was at The Rockefeller University in New York and peered through his microscope at squamous cell carcinoma (SCC), both the diabolical complexity—and the beauty—of this common form of skin cancer caught his eye.

Schober wasn’t the only one who found the image compelling. A panel of judges from the National Institute of General Medical Sciences and the American Society for Cell Biology chose to feature it in their Life: Magnified exhibit, which recently opened at the Washington Dulles International Airport.

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Personalized Cancer Vaccine Enters Human Trials

Photo of a researcher looking at a silver disc held by a curved hemostat

Caption: The new melanoma vaccine, which is implanted beneath the skin, is now being tested in human trials.
Credit: Wyss Institute and Amos Chan

This aspirin-sized disk is the first therapeutic cancer vaccine implanted beneath the skin [1]. We know it can eradicate melanoma in mice—the deadliest form of skin cancer—with impressive efficacy [2]. Now, it’s being tested in human trials. Continue reading