Articles

Disruption of a crucial cellular machine may kill the engine of deadly cancers

By Ruth SoRelle, M.P.H.

Cancer resembles a runaway car with a gas pedal stuck to the floor, hurling out of control.

Most targeted cancer therapies seek to fix the gas pedal itself, and thus thwart the aggressive behavior of the tumor. In many types of cancers, the “pedal” cannot be repaired, requiring alternatives. A team at Baylor College of Medicine has discovered a way to step on the brakes of some of the deadliest cancers.

Tiffany Hsu, an M.D./Ph.D student in the Medical Scientist Training Program, and lead author of the study, with Dr. Trey Westbrook.

Tiffany Hsu, an M.D./Ph.D student in the Medical Scientist Training Program, and lead author of the study, with Dr. Trey Westbrook.

Cancer gene MYC

“Almost 30 percent of all malignancies are driven by the cancer gene MYC. No one has been able to turn this gene off, and thus patients with MYC-driven cancers often lack effective therapies,” said Dr. Thomas (Trey) F. Westbrook, associate professor in the departments of biochemistry and molecular biology and molecular and human genetics at Baylor. “Like killing the engine of a runaway car, we have found a new way to kill cancers driven by MYC. We can do this by inhibiting a molecular machine within the cancer cell called the spliceosome.” A report on their work appears online in the journal Nature.

Westbrook and colleagues have discovered that MYC-driven cancers depend on the spliceosome to survive.

Spliceosome

“The spliceosome is a complex machine composed of many proteins,” said Tiffany Hsu, an M.D./Ph.D student in the Medical Scientist Training Program and lead author of the study. “This machine helps cancers ‘read’ their instruction manual by deleting unnecessary steps. When we inhibit the spliceosome, cancers can no longer understand their instructions for growth and survival.”

In their study, Westbrook, Hsu and colleagues found that inhibition of the spliceosome using a new drug kills tumor cells but leaves noncancerous tissues unaffected in mouse models.

“This study is a promising step towards helping patients with deadly cancers driven by MYC. We’re also excited to discover a new side to the MYC oncogene, which is one of the most intensely studied but enigmatic cancer genes,” said Hsu.

 

Rewires the cancer cell

MYC rewires the cancer cell, and changes many things like production of the building blocks that every tumor cell needs. But this rewiring also confers new stresses and new vulnerabilities in cancer cells.

“If we could learn how to exacerbate those stresses, we could kill the cancer cell without harming normal tissues,” said Westbrook, also a member of the Dan L. Duncan Cancer Center, an NCI-Designated Comprehensive Cancer Center, at Baylor. “The spliceosome may be a critical piece of the puzzle.”

While spliceosome inhibitors are unlikely to provide an answer to all cancers, they are promising candidates for some aggressive malignancies like triple negative breast cancer, a common and particularly virulent form of the disease.

Others who took part in this work include Lukas M. Simon, Nicholas Neill, Christopher S. Bland, Gloria V. Echeverria, Tingting Sun, Sarah J. Kurley, Siddhartha Tyagi, Kristen L. Karlin, Rocio Dominguez-Vidaña, Alexander Renwick, Kathleen Scorsone, Ronald J. Bernardi, Samuel O. Skinner, Antrix Jain, Mayra Orellana, Ido Golding, Sung Y. Jung, Joel R. Neilson Xiang H.-F. Zhang, Thomas A. Cooper and Chad Shaw, all of Baylor; Richard Marcotte, Azin Sayad and Benjamin G. Neel of Princess Margaret Cancer Centre at the University Health Network in Toronto, Canada; Jessica D. Hartman of Humacyte in Morrisville, North Carolina, Chandraiah Lagisetti and Thomas R. Webb of Center for Chemical Biology, Bioscience Division, SRI International in Menlo Park, California.

Funding for this work came from the Adrienne Helis Melvin Medical Research Foundation; the National Cancer Institute (Grant P30CA125123 and 1F30CA180447) and the National Institutes of Health (Grant P30AI036211 and S10RR024574 and Grant 1R01CA178039 and U54-CA149196), the Cancer Prevention and Research Institute of Texas (Grant RP120583 and RP101499), the Gillson Longenbaugh Foundation, Alex’s Lemonade Stand Foundation, the Susan G Komen for the cure (Grant KG090355) and the U.S. Department of Defense Cancer Research Program (Grant BC120604).

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