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Breakthrough model for human cancer may improve development of cancer drugs; study in PNAS
April 07, 2009AVEO Pharmaceuticals, Inc., a biopharmaceutical company leveraging breakthrough discoveries in cancer biology to discover, develop and commercialize targeted oncology therapies, today announced findings from its novel human-in-mouse (HIM) cancer model system, in which AVEO successfully created invasive human tumors from primary human breast tissue that develop over time in mice and mimic human tumor behaviors and response. The findings were published this week in the Early Edition of the Proceedings of the National Academy of Sciences.
More than 95 percent of oncology drugs entering the clinic fail, due in large part to the lack of predictive animal models in the preclinical development phases. AVEO scientists have developed a sophisticated cancer biology platform that provides models of human cancer more relevant than traditional mouse models known as xenografts. In the AVEO HIM model, normal human breast tissue is engineered to express oncogenes and is then introduced into mice where it forms human breast tissue in the mouse mammary microenvironment. The tumors which then develop spontaneously acquire common and distinct mutations during tumor progression. This process results in human tumors in mice that reflect their human counterparts in that they differ slightly from one instance to another, exhibiting natural genetic variation akin to that seen in patients.
"Historically, the xenograft models created to analyze how human cancers behave have not been accurate predictors of human responses to various therapeutic agents," said Robert A. Weinberg, Ph.D., member, Whitehead Institute and professor of biology, MIT. "In contrast, tumor development in the HIM model proceeds through defined histological stages of hyperplasia, from ductal carcinoma in situ (DCIS) to invasive carcinoma. Moreover, HIM tumors display characteristic responses to a targeted therapy known to be effective in humans, specifically Herceptin. This represents a big step forward in developing xenograft models that will accurately predict patient responses to agents that are in preclinical development. The HIM model is an exciting, experimentally tractable human in vivo system that holds great potential for advancing our basic understanding of cancer biology and for the discovery and testing of targeted therapies."
By employing a tissue recombinant system and a gene transduction system, researchers assessed the in vivo biological consequences of specific genetic alterations in the reconstituted breast tissue. Introduction of different combinations of oncogenes, such as HER2, KRAS, PI3 kinase and p53, into the tissue enabled the researchers to dissect the contribution of each gene to human tumor formation in the model.
The authors also demonstrated the utility of the HIM models for drug efficacy testing by treating the HER2 driven breast tumors with different HER2 antagonists. The resulting potent inhibition of HIM tumor growth correlates with what has been observed in the clinic.
"With the increasing knowledge of specific genetic alterations in breast cancer, there is now a significant opportunity to correlate activity of anticancer agents with specific genetic alterations in tumors," added Murray O. Robinson, Ph.D., senior vice president, oncology at AVEO. "Our proprietary models provide a defined genetic context in which to validate cancer gene candidates, determine their biological roles in various stages of cancer progression and test targeted therapies. We have been very encouraged by the similarity to human patients in response to widely used breast cancer agents."
Pure Communications Inc.
By employing a tissue recombinant system and a gene transduction system, researchers assessed the in vivo biological consequences of specific genetic alterations in the reconstituted breast tissue. Introduction of different combinations of oncogenes, such as HER2, KRAS, PI3 kinase and p53, into the tissue enabled the researchers to dissect the contribution of each gene to human tumor formation in the model.
The authors also demonstrated the utility of the HIM models for drug efficacy testing by treating the HER2 driven breast tumors with different HER2 antagonists. The resulting potent inhibition of HIM tumor growth correlates with what has been observed in the clinic.
"With the increasing knowledge of specific genetic alterations in breast cancer, there is now a significant opportunity to correlate activity of anticancer agents with specific genetic alterations in tumors," added Murray O. Robinson, Ph.D., senior vice president, oncology at AVEO. "Our proprietary models provide a defined genetic context in which to validate cancer gene candidates, determine their biological roles in various stages of cancer progression and test targeted therapies. We have been very encouraged by the similarity to human patients in response to widely used breast cancer agents."
Pure Communications Inc.
Cancer Biology Current Events and Cancer Biology News RSSSkin cells may provide early warning for cancer risk elsewhere in body
While some scientists have argued that cancer is such a complex genetic disease that you'd have to sequence a person's complete genome in order to predict his or her cancer risk, a University of California, Berkeley, cell biologist suggests that the risk may be more simply determined by inexpensively culturing a few skin cells.
October 15, 2009 Loss of Tumor-Suppressor and DNA-Maintenance Proteins Causes Tissue Demise, Penn Study Finds
A study published in the October issue of Nature Genetics demonstrates that loss of the tumor-suppressor protein p53, coupled with elimination of the DNA-maintenance protein ATR, severely disrupts tissue maintenance in mice. As a result, tissues deteriorate rapidly, which is generally fatal in these animals. In addition, the study provides supportive evidence for the use of inhibitors of ATR in cancer therapy.
Bioluminescence imaging used for eye cancer detection
At the moment, doctors rely on biopsy analysis to determine the progression of eye cancer. However, researchers now believe that a new technology, bioluminescence imaging (BLI), will allow doctors to detect tumors earlier and quickly choose a method of treatment that doesn't necessarily involve eye surgery.
Studying cancer in pet dogs to find new treatments for human patients
A team of scientists at the National Cancer Institute (NCI) in Bethesda, USA, says that studying pet dogs with cancer could yield valuable information on how to diagnose and treat human cancers.
New Chemo Cocktail Blocks Breast Cancer Like a Fence
Think of a protective fence that blocks the neighbor's dog from charging into your backyard. The body, too, has fences -- physical and biochemical barriers that keep cells in their place.
Molecular imaging holds promise for early intervention in common uterine cancer
A promising new molecular imaging technique may provide physicians and patients with a noninvasive way to learn more information about a type of cancer of the uterus lining called "endometrial carcinoma"-one of the most common malignant female tumors.
Expert calls for new cancer research priorities
Cancer research is too focused on new drug development, while not enough money and effort is being devoted to pursuing important advances in knowledge likely to have the biggest impact on combating the disease in the next few decades, a leading research policy expert says, adding that a major shift in research priorities will be crucial to the ability to cope with the coming wave of cancer cases.
Prodrug could help curb skin toxicity related to EGFR-inhibiting cancer drugs
There may be a way around the harsh skin toxicity associated with a widely used cancer drug, according to a study published online this week in Cancer Biology and Therapy by researchers from City of Hope and the Kimmel Cancer at Jefferson.
NIH study reveals new genetic culprit in deadly skin cancer
Drawing on the power of DNA sequencing, National Institutes of Health researchers have identified a new group of genetic mutations involved in the deadliest form of skin cancer, melanoma.
New DNA Test Uses Nanotechnology to Find Early Signs of Cancer
Using tiny crystals called quantum dots, Johns Hopkins researchers have developed a highly sensitive test to look for DNA attachments that often are early warning signs of cancer.
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