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December 29th, 2016

Drug combo stems tumor growth in lung cancer

By Nicole Brudos Ferrara

Researchers on Mayo Clinic's campus in Jacksonville, Florida, have shut down one of the most common and lethal forms of lung cancer by combining the rheumatoid arthritis drug auranofin with an experimental targeted agent.

The combination therapy worked in a laboratory study to stop lung adenocarcinoma associated with mutation of the KRAS gene. The study was published in the March 14, 2016, issue of Cancer Cell.

Alan Fields, Ph.D.

Alan Fields, Ph.D.

"If our approach works in KRAS-mediated lung adenocarcinoma, it may work in other KRAS-mediated cancers, such as pancreatic cancer and colon cancer, as well as other cancer types," said the study's senior author, Alan P. Fields, Ph.D., a cancer biologist in the Department of Cancer Biology at Mayo Clinic in Jacksonville, Florida, and the Monica Flynn Jacoby Professor of Cancer Research.

Based on this and other preclinical research from Dr. Fields' team, Mayo Clinic is conducting early-phase clinical trials to test the effectiveness of auranofin alone and in targeted combinations in patients with KRAS-mediated lung adenocarcinoma, ovarian cancer, and another common lung cancer called lung squamous cell carcinoma.

The current study:

  • Identified the cancer stem cells that drive development of cancer cells in KRAS-mediated lung adenocarcinoma
  • Identified a major signaling pathway, or set of molecular mechanisms, that stimulates the growth of those cancer stem cells
  • Showed how combining auranofin and the experimental agent shut down that pathway and may be an effective treatment approach

"Cancer stem cells are the really bad actors in many cancers," Dr. Fields said. "Cancer stem cells initiate cancer development, drive its growth and metastasis, and also develop resistance to treatments.

"Conventional chemotherapy can effectively kill non-stem cancer cells, but cancer stem cells often survive," he said. "Then, once therapy is stopped, these cancer stem cells can re-establish the tumor and cause a relapse."

The current research study built on previous research from Dr. Fields' laboratory that:

  • Identified protein kinase C iota (PKCiota) as an oncogene — a gene that has the potential to cause cancer — and linked it to multiple forms of cancer
  • Showed that auranofin inhibits PKCiota and may be useful in treating cancer
  • Found that PKCiota activates a second oncogene, SOX2, to stimulate cancer stem cell growth in lung squamous cell carcinoma

Dr. Fields said the current study, surprisingly, found that PKCiota regulates cancer stem cells through a different pathway in KRAS-mediated lung adenocarcinoma than it does in lung squamous cell carcinoma. It also activates a different oncogene, NOTCH3. This enabled an individualized treatment approach.

Using this knowledge, Dr. Fields' team treated KRAS-mediated lung adenocarcinoma tumors in mice with auranofin and a NOTCH3 inhibitor and found that these two drugs work better together than either drug did alone.

"This research indicates auranofin might be useful in treating many different cancer types," Dr. Fields said. "By combining it with a second agent targeted to the specific signaling pathway, we hope to fine-tune therapy to the particular vulnerabilities of each type of tumor. This approach may be useful in multiple forms of lung, ovarian, pancreatic and possibly head and neck, cervical, and several other cancers."

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This article was originally published in Forefont, Mayo Clinic Cancer Center's online magazine.

Tags: Alan Fields, auranofin, cancer stem cells, chemotherapy, Findings, Florida, Forefront, KRAS gene, lung cancer, PKCiota

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