ddn Cancer Research News Exclusive: Collaring colorectal cancer

Mount Sinai researchers discover that soy-derived genistein can impact a signaling pathway responsible for driving growth of colorectal cancer

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NEW YORK—Mount Sinai announced at this year's AmericanAssociation for Cancer Research 2013 Annual Meeting novel research that couldoffer a new treatment for colorectal cancer: genistein, a natural supplementfrom soy.
Genistein is a soy-derived isoflavone, and the NationalCancer Institute also identifies it as a phytoestrogen, plant-derivedestrogen-like chemicals found in plant foods, and notes that it displaysantineoplastic activity and can disrupt signal transduction and induce celldifferentiation. Genistein is used commercially as a supplement for menopauseand female health issues.
Colorectal cancer's growth is primarily driven by cellularsignaling in the Wnt pathway, a network of proteins pivotal to cellular growth.More than 85 percent of colon and rectal cancers display hyperactivity of thissignaling pathway. In their work, the scientists—led by Randall Holcombe, M.D.,and Sofya Pintova, M.D., both of Mount Sinai—treated colon cancer cell lineswith genistein, which blocked hyperactivity of the Wnt pathway and resulted ininhibition of cell growth.
Their work with genistein was inspired by previous work withnatural products, says Holcombe, specifically resveratrol, an antioxidantfounds in grapes and red wine and known to play a role in wine's positivereputation in preventing heart disease. Holcombe says they looked atresveratrol's effects on colon cancer prevention, adding that he has conductedresearch in natural products for some time. Their interest in genistein beganas a result of the suggestion that it might affect the Wnt pathway.
In their research, Holcombe says one of the most interestingdiscoveries is that genistein reduced proliferation in several types of coloncancer cells, and was equally effective in cell lines with and without the Wntpathway mutation.
"There seemed to be a correlation between the reduction ingrowth and the effects on the Wnt pathway, which suggests that the mechanism ofaction of the genistein at least in part may be through inhibition of the Wntpathway," explains Holcombe, professor of Medicine in the Division of Hematologyand Oncology at the Icahn School of Medicine at Mount Sinai.
Genistein's potential as a therapeutic isn't confined tocolorectal cancers, either. Holcombe notes that several other types of cancerpresent with activation of the Wnt pathway, including a small subset of breastcancers, sarcomas, some liver cancers and some cancers of the gastrointestinaltract such as stomach cancers. Given its estrogen-like properties, however, hecautions that it wouldn't be recommended for breast cancer.
"If you look at colon cancer, it's true about 85 percenthave activation of this Wnt signaling pathway, and that activation occursbecause of a mutation in the cancer cells," says Holcombe. "Genistein appearsto work on colon cancer cells, at least from our work in the laboratory,whether these cells have this activating mutation or not, which is a goodproperty … so we think it may be useful for patients with colon cancer assomething that may be additive to the effects of other chemotherapy. And infact, there is some other literature that suggests that genistein may actuallybe not just additive but also synergistic with certain types of chemotherapy.So we're hopeful that the addition of genistein to a treatment regimen mayactually lead to improved response rates for patients with metastatic colon orrectal cancer."
As for whether genistein might have any preventive effects,Holcombe says the answer to that question is "perhaps." It's been tested as apreventative in prostate cancer because of its estrogen-like properties, butthe studies "were not definitive," and he adds that determining whether itcould play a role in colon cancer prevention will "take some additional studyto sort out."
Natural products such as genistein will most likely continueto play a role in medicine, particularly cancer, according to Holcombe.
"I think that natural products probably in the future willhave its greatest role if we can identify where they work for cancerprevention, because they tend to have a very low side effect profile, and soit's something that could be utilized in that setting," he explains. "Forcancer treatment, I think the role of natural products will probably be not asan individual therapy for cancer, because I don't think they have enoughactivity in and of themselves to provide that much benefit, but more as anadjunctive treatment along with other cytotoxic chemotherapies or targetedtherapies for cancer."
The researchers will continue this research by initiating aclinical trial later this year evaluating genistein in combination withchemotherapy for patients with metastatic colon and rectal cancer, saysHolcombe. They will also do additional lab work "to look at the potentialsynergy between genistein and chemotherapy medications," identify whichcombinations might work well together and then investigate them further.
"Genistein is a natural product with low toxicity and fewside effects, and our research shows that it may be beneficial in treatingcolorectal cancer," said Holcombe. "This is an exciting area of research and welook forward to studying the benefits of this compound as an adjunctivetreatment in colorectal cancer in humans."

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