January 28, 2015

Discoveries in Oncotargeting Aid the Fight Against Colon Cancer

Development of a novel approach appears to inhibit oncogene pathways

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Despite improvements in the treatment of colon cancer, detection often does not occur until the disease is in an advanced stage, which increases mortality. For instance, once colon cancer has spread to distal organs, the five-year survival is only approximately 12 percent.

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But innovative research from Cleveland Clinic examines the role of a new approach to block specific molecular pathways that affect tumor growth — potentially giving clinicians and patients an additional tool for treating cancer.

Pathogenic Pathways

Over the past decade, there has been increased interest in investigating molecular pathways that affect the activation and suppression of oncogenes, or genes with the potential to lead to cancer. Identification of oncogene signaling pathways may be particularly informative for altering their genetic transcription. In colon cancer, a family of transcription factors called GLI — and specifically GLI1 and GLI2 — have become a novel and potentially important focus of molecular research to possibly improve therapeutic intervention and hence prognosis.

“GLI1 and GLI2 are oncogenes, so when aberrantly activated, they can transform cells, can cause cancer, they drive proliferation and they turn on genes involved in cell growth,” explains Janet Houghton, PhD, of the Department of Cancer Biology at Cleveland Clinic’s Lerner Research Institute. “GLI 1 and 2 are activated in epithelial cancers, like GI cancer and colon cancer, as well as in lung cancers, pancreatic cancers, brain tumors, melanoma and pediatric solid cancers.”

GLI are located at the distal end of a signaling pathway called Hedgehog, which plays a vital role in embryonic cellular function and organ development and is expressed at low levels in adult tissues. But in cancer, this pathway is always turned on, leading to the activation of the infamous GLI genes. Clinical trials of pharmaceutical inhibitors of Hedgehog have been mixed, due to an additional route that allows GLI to become activated while circumventing the Hedgehog pathway: two genes called KRAS and BRAF.

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“These genes are mutated in colon cancer — in about 50 percent of cases, in fact — and these directly activate GLI genes,” says Dr. Houghton. “So this could impact a wide variety of cancers because not only are GLI1 and 2 present in many cancers and constituently activated by KRAS, but KRAS mutations also are in one-third of all human cancers. People have been trying to develop inhibitors of KRAS, and it’s just been very elusive.”

A New Target

Given its prominent role in Hedgehog signaling and in oncogenic KRAS and BRAF function, Dr. Houghton recently investigated a novel compound to directly target GLI, called GANT61. In seven human colon carcinoma cell lines, GANT61 successfully induced extensive cell death, thus inhibiting GLI transcription and oncogenic signaling via convergence on GLI.

“For clinicians, this could represent a new way of thinking about how to treat these types of cancers,” Dr. Houghton says. “GLI is helping to drive [tumor] growth because it activates genes that drive proliferation. So inhibiting its function with GANT61 demonstrates that the GLI genes are pivotal in controlling aberrant cell growth in cancers.”

The next step for Dr. Houghton will be to further examine the role of GANT61 in targeting GLI by more clearly identifying its underlying mechanisms of action. A drug discovery initiative is also being developed to determine if GANT61 can be improved upon — such as whether it can be modified to make it water-soluble or if its binding can be enhanced to develop a suitable drug for therapeutics application. The hope is that identification of GLI as a therapeutic target can inform pharmaceutical development for not just colon cancer but also the numerous other carcinomas in which GLI and KRAS are implicated.

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“This research has brought us into a whole new world of transcription regulation and how that’s inhibited,” says Dr. Houghton. “It’s going to be a fascinating journey.”

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