Researchers create cellular 'ORACLs' to aid drug discovery

December 14, 2015

A team of researchers at UC San Francisco has devised a new approach for early stage drug discovery that uses techniques from the world of computer vision in combination with a powerful new tool: a lineage of genetically modified cancer cells in a dish that change their appearance when treated with drugs targeting common disease pathways.

The researchers hope to employ these cells -- in combination with algorithms akin to those used by face-recognition software -- to quickly organize the hundreds of thousands of molecules in institutional compound libraries according to their biological function, greatly facilitating the search for new and better drugs for cancer and other diseases. For this reason, they dubbed the cells ORACLs (Optimized Reporter cell lines for Annotating Compound Libraries).

A paper describing the new approach was published online Dec. 14, 2015 in the journal Nature Biotechnology.

Co-senior authors Steven Altschuler, PhD, and Lani Wu, PhD, are professors of pharmaceutical chemistry in the UCSF School of Pharmacy and conducted the initial research in this area while at the University of Texas Southwestern Medical Center. The pair envision making drug discovery more like the field of genomics, where researchers have spent decades annotating large genomic databases as more and more functions are discovered for individual genes and regulatory elements. As a result of this community effort, researchers can now rapidly identify particular genes of interest for more targeted investigations.

Using ORACLs to functionally annotate existing compound libraries could have similar benefits, enabling researchers to quickly identify drugs that are clinically relevant for specific disease pathways, and significantly streamlining the way scientists use the shared drug discovery facilities, or cores, which are common in academic research.

"Drug screening cores are very busy - they run continuously," Wu said. "The problem is that screening results generally cannot be reused. When you have a new biological target you want to hit with a drug, you have to go and screen the whole compound library again."

Shape-shifting cells reveal drug mechanisms

Researchers commonly screen for effective drugs using "reporter cells," which are carefully designed to change their behavior or appearance in response to a successful treatment. But the creation of an ORACL - a single reporter cell line capable of distinguishing between multiple common drug classes - required a different approach.

"We didn't know how to design such a versatile reporter cell based on our existing biological knowledge," said Chien-Hsiang "Charles" Hsu, a graduate student in the Altschuler and Wu lab and co-lead author on the new study. "So we thought, why not just randomly tag proteins and screen the cells with drugs to see which line could produce the response that fit our goal?"

The researchers created an assortment of 93 cell lines, based on an existing line of lung cancer cells, by tagging randomly selected genes with a fluorescent marker. They treated cells from each of these lineages with a panel of 30 compounds belonging to six commonly used classes of cancer drugs, then analyzed images of the cells with custom algorithms. As the team had hoped, different drugs caused cells to change their shape and pattern of fluorescence in distinct ways that enabled the software to deduce which type of drug had been applied.

As anticipated, some cell lines were more informative than others: To the researchers' delight, one cell line proved capable of distinguishing between the six drug classes with 94 percent accuracy. Some of the more subtle aspects of the cells' characteristic responses to different drug types required the computer algorithms to detect, but others were obvious under the microscope: DNA damaging drugs caused cells to swell, while HDAC inhibitors produced a spiky appearance. MTOR inhibitors produced dim fluorescence throughout the cell, while treatment with hsp90 inhibitors resulted in fluorescent speckles within the cytoplasm.

The researchers had found their ORACL.

Oracular cells could screen compound libraries for overlooked drugs

To test their ORACL cells, the team screened through more than 10,000 small molecules of unknown function from several institutional compound libraries. Their analysis identified 106 molecules whose effects on the cells matched those of the "training" drugs that had been used to initially select the ORACL, and further experiments confirmed that at least 90 of these matches affected the same biological pathway as the training drug.

To the researchers' surprise, ORACL cells also produced characteristic responses to a slew of additional compounds, some of which turned out to belong to drug classes not included in the original training set, including ER and Aurora Kinase inhibitors, glucocorticoid steroids, ATPase inhibitors, and dihihydrofolate reductase inhibitors, as well as a dozen other groups of molecules whose shared biological function is still not known.

"What's amazing," said Altschuler, "is that we were able to do one screen, one time, and fish out molecules that were in many different diverse classes at once."

The researchers are currently scaling up their screens to enable rapid annotation of compound libraries containing hundreds of thousands molecules. They hope that ORACLs will be adopted to identify new compounds that hit biological pathways where current drugs have too many side effects or miss certain patient populations. They could find compounds that affect pathways affected by few known drugs or even drugs whose effects seem far from any known biological pathway.

"These are really early steps in drug discovery," Altschuler said. "We hope finding more high quality compounds will make all the later steps more efficient. Currently the process takes billions of dollars over many, many years. Wouldn't it be nice to make that easier?"
Major funding for the research was provided by the National Institutes of Health.

Jungseog Kang, PhD was co-lead author on this study and is now at New York University-Shanghai. Additional authors on the study are: Qi Wu; Shanshan Liu, PhD; Adam D. Coster, PhD; and Bruce A. Posner, PhD, all at the University of Texas Southwestern Medical Center in Dallas. The authors have filed for a patent on the techniques described in this study.

UC San Francisco (UCSF) is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care. It includes top-ranked graduate schools of dentistry, medicine, nursing and pharmacy, a graduate division with nationally renowned programs in basic, biomedical, translational and population sciences, as well as a preeminent biomedical research enterpriseand UCSF Health, which includes two top-ranked hospitals, UCSF Medical Center and UCSF Benioff Children's Hospital San Francisco, as well as other partner and affiliated hospitals and healthcare providers throughout the Bay Area.

University of California - San Francisco

Related Cancer Articles from Brightsurf:

New blood cancer treatment works by selectively interfering with cancer cell signalling
University of Alberta scientists have identified the mechanism of action behind a new type of precision cancer drug for blood cancers that is set for human trials, according to research published in Nature Communications.

UCI researchers uncover cancer cell vulnerabilities; may lead to better cancer therapies
A new University of California, Irvine-led study reveals a protein responsible for genetic changes resulting in a variety of cancers, may also be the key to more effective, targeted cancer therapy.

Breast cancer treatment costs highest among young women with metastic cancer
In a fight for their lives, young women, age 18-44, spend double the amount of older women to survive metastatic breast cancer, according to a large statewide study by the University of North Carolina at Chapel Hill.

Cancer mortality continues steady decline, driven by progress against lung cancer
The cancer death rate declined by 29% from 1991 to 2017, including a 2.2% drop from 2016 to 2017, the largest single-year drop in cancer mortality ever reported.

Stress in cervical cancer patients associated with higher risk of cancer-specific mortality
Psychological stress was associated with a higher risk of cancer-specific mortality in women diagnosed with cervical cancer.

Cancer-sniffing dogs 97% accurate in identifying lung cancer, according to study in JAOA
The next step will be to further fractionate the samples based on chemical and physical properties, presenting them back to the dogs until the specific biomarkers for each cancer are identified.

Moffitt Cancer Center researchers identify one way T cell function may fail in cancer
Moffitt Cancer Center researchers have discovered a mechanism by which one type of immune cell, CD8+ T cells, can become dysfunctional, impeding its ability to seek and kill cancer cells.

More cancer survivors, fewer cancer specialists point to challenge in meeting care needs
An aging population, a growing number of cancer survivors, and a projected shortage of cancer care providers will result in a challenge in delivering the care for cancer survivors in the United States if systemic changes are not made.

New cancer vaccine platform a potential tool for efficacious targeted cancer therapy
Researchers at the University of Helsinki have discovered a solution in the form of a cancer vaccine platform for improving the efficacy of oncolytic viruses used in cancer treatment.

American Cancer Society outlines blueprint for cancer control in the 21st century
The American Cancer Society is outlining its vision for cancer control in the decades ahead in a series of articles that forms the basis of a national cancer control plan.

Read More: Cancer News and Cancer Current Events is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to