Cancer drug works by overactivating cancer gene: melanoma tumors carry enemy within, suggesting new treatment strategy

Abstract

University of Michigan Comprehensive Cancer Centerresearchers have discovered that bortezomib, a promising cancer drug,is able to strike a blow against melanoma tumor cells by revving upthe action of a cancer-promoting gene.

They say the laboratory-based findings suggest a novel treatmentstrategy that might someday prove effective against many types ofcancer: Push cancer cells into overdrive, so that they self-destruct.

The U-M scientists found that bortezomib, a drug approved by the FDAto treat advanced multiple myeloma, is able to selectively inhibitmelanoma tumor cells because it causes the c-MYC oncogene tooverproduce a cell-death promoter called NOXA. Their results placec-MYC and NOXA, well studied among cancer researchers, in a newlight. The study appeared online ahead of print in the Proceedings ofthe National Academy of Sciences.

"Our data suggest a different approach to treat cancer," says MariaS. Soengas, Ph.D., the senior author of the study. Soengas is anassistant professor of dermatology at the U-M Medical School and amember of the U-M Comprehensive Cancer Center.

Many cancer treatments aim to block specific oncogenes, genes thatwreak havoc with the normal signals that dictate when cells multiplyand die.

The thinking is that if oncogenes are disabled, cancer cells can'tproliferate uncontrollably and spread. However, scientists know thatoncogenes can play dual roles: They can cause tumor cells to rapidlydivide, but can also step up programmed cell death, or apoptosis.

Therefore, "an alternative treatment could be to actually exacerbateoncogene function, to promote such a dysregulation of cell cycleprogression and activation of apoptotic proteins that tumor cellsultimately die," says Soengas.

Melanoma tumor cells manage to resist most cancer drugs. For morethan 30 years, the prognosis for patients with advanced melanoma hasnot significantly improved. Soengas likens the melanoma tumor cell'sdefenses to a heavy suit of armor that so far has blockedresearchers' attempts to penetrate it. Now it appears that the tumorcells have an enemy within.

In human melanoma cells cultured and manipulated in the laboratory,Soengas and her team have studied bortezomib and other drugcandidates to understand their molecular modes of action.

Bortezomib belongs to a class of drugs called proteasome inhibitorsthat show promise in attacking many types of tumors. But how thedrugs direct their biggest punch at tumor cells, with less effect onnormal ones, has puzzled scientists - the cell actors they target,proteasomes, are widespread and essential to normal cells.

Soengas and colleagues reported in 2005 that bortezomib appears tocombat tumor growth by increasing the activity of a cell-deathpromoter called NOXA in tumor cells, but not in normal cells. In thenew study, the U-M scientists report that the force behind thisselective uptick in NOXA, and the resulting cell death, surprisinglyturned out to be the oncogene c-MYC.

The discovery of the oncogene's role in bortezomib's action hasimplications for other cancers besides melanoma, says MikhailNikiforov, Ph.D., the paper's first author. The Soengas and Nikiforovgroups collaborated to elucidate molecular mechanisms ofc-MYC-mediated regulation of NOXA in melanoma and other tumor celltypes. Nikiforov is an assistant professor of dermatology at the U-MMedical School and a member of the U-M Comprehensive Cancer Center.

The findings lay the groundwork for more studies to improvebortezomib's effectiveness in treating cancers and to reduce itstoxicity in normal cells, Soengas says.

"Now we can rationally design drugs that enhance bortezomib's actionand favor NOXA production," she says. "Improvements might make itpossible to give lower doses of the drug for a shorter time."

These improvements to bortezomib treatment, as well as other drugsthat could take advantage of the study results, will take years oftesting before they can possibly help patients. Soengas and hercolleagues are collaborating with other U-M scientists on severalprojects, including one led by Shaomeng Wang, Ph.D., associateprofessor of hematology/oncology and pharmacology, to design drugsthat will favor the effects of NOXA.

Clinical trials to test bortezomib's effects on other types of tumorsare under way at the U-M and around the country.

Citation: Nikiforov et al. 2007-08380 v2, Proceedings of the NationalAcademy of Sciences

The research was funded by the National Institutes of Health, theDermatology Foundation and the Elsa U. Pardee Foundation.

Other U-M authors of the study include: MaryBeth Riblett, Wen-HuaTang, Vladimir Gratchouck, Dazhong Zhuang, Yolanda Fernandez, MoniqueVerhaegen, Sooryanarayana Varambally, Arul M. Chinnaiyan and AndrzejJ. Jakubowiak.