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Novel chemical that controls cell behavior

GTPases act as chemical switches controlling cell shape changes through growth stages, and stickiness as they migrate. Now, a newly identified chemical compound might interrupt these behaviors before metastases migration can begin.

The spread of the original cancer tumor kills most people. That’s why cancer researchers vigorously search for drugs that prevent cancer's spread.

The research team co-led by Angela Wandinger-Ness, PhD, and Larry Sklar, PhD, at the University of New Mexico Cancer Center has found a chemical compound that appears to control cell migration and adhesion, two important characteristics of metastatic cancer cells. The team published February 4, 2013 in the Journal of Biological Chemistry, describing how the first-in-class compound acts on various cells.

Dr. Wandinger-Ness, a UNM Professor of Pathology and Director of the Fluorescence Microscopy and Cell Imaging Shared Resource, studies proteins called GTPases.

GTPases act as chemical switches to control cell behavior:
how much a cell grows, what shape it assumes when it
enters the next growth stage, and how tightly it sticks
to its surroundings, among hundreds of other possibilities.

Dr. Wandinger-Ness was interested in how the GTPase
known as Cdc42 controls cell migration and cell adhesion.

“It’s an important target in many diseases, cancer being just one. But there were no compounds that target this GTPase.”
In a collaboration with Dr. Sklar and Tudor Oprea, MD, PhD,
to find a compound that did, the team was successful.

Dr. Sklar is a UNM Professor of Pathology and co-Leader of the Cancer Biology and Biotechnology Research Group at the UNM Cancer Center. He created and now oversees the UNM Center for Molecular Discovery. Dr. Oprea is a UNM Professor of Medicine and co-Director of the Flow Cytometry & High Throughput Screening Shared Resource at the UNM Cancer Center, and he analyzed Cdc42 using three-dimensional molecular rendering software.

The team used Dr. Oprea’s analysis of Cdc42 to visualize how a compound might stifle its' activity. Then they searched for such a compound in the UNM Molecular Discovery library.

The search process was akin to finding a needle in a haystack. However, using the latest high throughput flow cytometry equipment and molecular rendering software available from the UNM Cancer Center, sped up their analysis significantly. They narrowed their search to a few hundred likely candidates and then tested those against several kinds of GPTases.

“From a purely discovery perspective, that’s a high impact, novel way to look for small molecules,” says Dr. Sklar. The compound they found is called CID2950007.

CID2950007 is structurally similar to NSAIDs
—non-steroidal anti-inflammatory drugs—
it restrains the Cdc42 GTPase from changing
a cell’s cytoskeleton.

Much like a skeleton gives a human body shape, a cell’s
cytoskeleton keeps the cell from collapsing in on itself.
The cytoskeleton also enables a cell to move by
growing amoeba-like legs called filopodia.

Cdc42 also helps to keep cells where they need to be by
enabling them to adhere more tightly to their surroundings.

So, while uncontrolled growth and movement are hallmarks of metastatic cancer cells, growth and adherence are important traits for healthy cells. Tightly controlling just how Cdc42 causes a cell to behave is crucial.

In their paper, the team of scientists report that CID2950007
was the only compound found that affected only the Cdc42
GTPase without affecting any other GTPases.

They also found that the compound works by changing the
physical structure of Cdc42—without destroying Cdc42—
which affects how it interacts with other cellular proteins.

Their studies showed that CID2950007 decreased filopodia
growth and cell adhesion in ovarian cancer cells,
preventing cell adhesion with white blood cells.

Also, their studies demonstrated that CID2950007 blocked
Hantavirus infection in monkey kidney cells.

By affecting the Cdc42 GTPase—thus the shape of the
cytoskeleton—CID2950007 has the potential to fight not only
cancer but also infectious diseases.

Human use of CID2950007 as a cancer drug is a long way off.

Before the Food and Drug Administration approves any drug for human use, it first requires the successful results of several toxicity and dose escalation studies on several types of animals. Then, the clinical trials process, which can take over 10 years, may begin.

“There are going to be a lot of side effects because these adhesion proteins have many other functions,” says Dr. Sklar. So refining CID2950007 into a drug will take further collaboration and studies before toxicity studies and dose escalation studies can begin.

To refine the compound, the UNM Cancer Center researchers will continue to collaborate with Jeffrey Aubé, PhD, Kansas University Distinguished Professor of Medicinal Chemistry, and Jennifer Golden, PhD, Assistant Director of the Specialized Chemistry Center at Kansas University.

Still, control of GTPase Cdc42 offers promise as a way to control cancer metastasis. Says Dr. Wandinger-Ness, “there’s a lot of enthusiasm for a compound like this — because there weren’t any. This is a first-in-class.”

Paper reference
“Characterization of a Cdc42 Inhibitor and its Use as a Molecular Probe” was published online in the Journal of Biological Chemistry on February 4, 2013 (http://www.jbc.org/) . Authors are: Lin Hong (University of New Mexico); S. Ray Kenney (Univerisity of New Mexico); Genevieve K. Phillips (UNM Cancer Center); Denise Simpson (Univerisity of Kansas); Chad E. Schroeder (Univerisity of Kansas); Julica Nöth (Univerisity of Kansas); Elsa Romero (University of New Mexico); Scarlett Swanson (University of New Mexico); Anna Waller (University of New Mexico); J. Jacob Strouse (University of New Mexico); Mark Carter (University of New Mexico); Alexandre Chigaev (UNM Cancer Center); Oleg Ursu (UNM Cancer Center); Tudor Oprea (UNM Cancer Center); Brian Hjelle (University of New Mexico); Jennifer E. Golden (Univerisity of Kansas); Jeffrey Aubé (Univerisity of Kansas); Laurie G. Hudson (UNM Cancer Center); Tione Buranda (University of New Mexico); Larry A. Sklar, co-senior author (UNM Cancer Center); Angela Wandinger-Ness, co-senior author (UNM Cancer Center).
The paper is available to the public at: http://www.jbc.org/content/early/2013/02/04/jbc.M112.435941.full.pdf+html

About the UNM Cancer Center
The UNM Cancer Center is the Official Cancer Center of New Mexico and the only National Cancer Institute-designated cancer center in the state. One of just 67 NCI-designated cancer centers nationwide, the UNM Cancer Center is recognized for its scientific excellence, contributions to cancer research and delivery of medical advances to patients and their families. Annual federal and private funding of over $65 million supports the UNM Cancer Center’s research programs. The UNM Cancer Center treats more than 65 percent of the adults and virtually all of the children in New Mexico affected by cancer, from every county in the state. It is home to New Mexico’s largest team of board-certified oncology physicians and research scientists, representing every cancer specialty and hailing from prestigious institutions such as MD Anderson, Johns Hopkins and the Mayo Clinic. Through its partnership with Memorial Medical Center in Las Cruces, the UNM Cancer Center brings world-class cancer care to the southern part of the state; its collaborative clinical programs in Santa Fe and Farmington serve northern New Mexico. The UNM Cancer Center also supports several community outreach programs to make cancer screening, diagnosis and treatment available to every New Mexican. Learn more at www.cancer.unm.edu.

UNM Cancer Center contact information
Dorothy Hornbeck, JKPR, (505) 340-5929, dhornbeck@jameskorenchen.com
Michele Sequeira, UNM Cancer Center, (505) 925-0486, msequeira@salud.unm.edu

Original article: http://cancer.unm.edu/2013/03/12/unm-cancer-center-scientists-discover-novel-chemical-that-controls-cell-behavior/