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Mayo Clinic Researchers Identify Biomarker for Smoker’s Lung Cancer

Mayo Clinic researchers have shown that a specific protein pair may be a successful prognostic biomarker for identifying smoking-related lung cancers. The protein — ASCL1 — is associated with increased expression of the RET oncogene, a particular cancer-causing gene called RET. The findings appear in the online issue of the journal Oncogene.

“This is exciting because we’ve found what we believe to be a ‘drugable target’ here,” says George Vasmatzis, Ph.D., a Mayo Clinic molecular medicine researcher and senior author on the study. “It’s a clear biomarker for aggressive adenocarcinomas. These are the fast-growing cancer cells found in smokers’ lungs.”

ASCL1 is known to control neuroendocrine cell development and was previously linked to regulation of thyroid and small cell lung cancer development, but not smoking-related lung cancer. The research also showed that patients with ASCL1 tumors with high levels of the RET oncogene protein did not survive as long as ASCL1 patients with low levels of RET.

When researchers blocked the ASCL1 protein in lung cancer cell lines expressing both genes, the level of RET decreased and tumor growth slowed. This leads researchers to believe this mechanism will be a promising target for potential drugs and a strong candidate for clinical trials.

The co-authors of the study include Farhad Kosari, Ph.D.; Cristiane Ida, M.D.; Marie Christine Aubry, M.D.; Lin Yang, Ph.D.; Irina Kovtun, Ph.D.; Janet Schaefer Klein; Yan Li, M.D.; Sibel Erdogan; Sandra Tomaszek, M.D.; Stephen Murphy, Ph.D.; Lynn Bolette; Christopher Kolbert; Ping Yang, M.D., Ph.D.; and Dennis Wigle, M.D., Ph.D., all of Mayo Clinic.

The research was supported by a Waterman Biomarker Discovery grant and by the Mayo Clinic Center for Individualized Medicine.

Study: ASCL1 and RET expression defines a clinically relevant subgroup of lung adenocarcinoma characterized by neuroendocrine differentiation [Oncogene]

Source: Mayo Clinic

Potential Clue Associated with Aggressive Prostate Cancer Identified by Rutgers Investigators

Prostate cancer is one of the most common forms of cancer in men and the leading cause of cancer deaths in white, African-American and Hispanic men, according to the Centers for Disease Control. Current treatment of prostate cancer targets androgens, hormones which promote the growth and spread of cancer cells. However, it remains unclear why, despite treatment, some prostate cancers progress and may become fatal. Researchers at Robert Wood Johnson Medical School, part of Rutgers, The State University of New Jersey, who are studying the underlying mechanisms that cause invasive tumor growth have identified a key transcription factor, a protein which regulates the flow of information from DNA, that is over-produced in treatment-resistant prostate cancer, as well as the two protein kinases that trigger the process. This finding, published and highlighted on the cover of the July issue of Molecular Cancer Research, a journal of the American Association for Cancer Research (AACR) could be utilized to develop treatments for prostate cancer that is resistant to current therapies.

The research team, led by Joseph Fondell, PhD, associate professor of pharmacology, found that in clinically localized human prostate cancer — cancer that is confined to the prostate and pelvic area — the key transcription factor termed MED1 is overexpressed, meaning that significantly more MED1 is produced than is typical. According to Fondell, the finding potentially could be used as a biomarker in cancer screenings, indicating to oncologists that the prostate cancer has become aggressive. “As MED1 is a known co-activator of androgen receptors, the overexpression of MED1 is thought to facilitate alternative gene expression patterns that drive treatment-resistant cancer cell growth in the prostate,” Fondell said.

“Our study showed for the first time that MED1 expression is elevated in malignant cells of a statistically significant number of patients with clinical prostate cancer and that this overexpression correlates with an increase in cancer cell growth and invasiveness,” said Feng Jin, PhD, a former graduate student in Fondell’s lab and first author on the study. “In addition to accelerated tumor growth, our study showed that overexpression of MED1 may also be involved with inflammation of the prostate.”

Further study of the process using mouse models that mimic human prostate cancer, showed that two protein kinases, ERK and PI3K/AKT, were overactive and responsible for MED1 overproduction, ultimately accelerating the progression and spread of prostate cancer.

“Whereas the current treatment approach for prostate cancer is to prohibit androgen production and signaling, our findings indicate that MED1 could represent a novel target for new therapies that stop the process at the molecular level, before prostate cancer can progress to an advanced stage,” added Fondell, who also is a member of Rutgers Cancer Institute of New Jersey.

Study: ERK and AKT Signaling Drive MED1 Overexpression in Prostate Cancer in Association with Elevated Proliferation and Tumorigenicity [Molecular Cancer Research]

Source: Robert Wood Johnson Medical School

Cancer Research Implies Future for Personalized Medicine, Reduction in Animal Testing

On August 6th, JoVE, the Journal of Visualized Experiments, published two new methods for scientists to study and treat tumor growth. The methods introduce a lab-born, human tissue structure with replicated human biochemistry – offering scientists the opportunity to grow, observe, and ultimately learn how to treat biopsied human tumor cells.

The University Hospital of Würzburg scientists behind the experiment have created a new version of the testing structures known as biological vascularized scaffolds (BioVaSc). Their three-dimensional human-tissue structures are the first of their kind to be built with multiple human cell types. The structures offer two methods for study: a three-dimensional (3D) static system for short term testing that is beneficial for microscopy imaging, and a dynamic system that introduces a flow-simulation to simulate actual conditions of the human body. This is especially helpful in long term studies of metastasis, or, the spreading of cancer cells through the human vascular system.

“Our 3D tumor model is reducing or even replacing animal experiments,” said engineer Jenny Reboredo. In their article, Reboredo and her colleagues explained that this human-tissue based testing system could eliminate the potential for the misinterpretation that often accompanies animal testing. Furthermore, this method solves the shortfalls of typical in-vitro testing, which is limited by the lack of intercellular interactions.

The authors also suggest that their use of primary cells derived from tumor biopsies is a “very important step towards personalized medicine.” With the method the team has created, a lab could in the future take a biopsy of a cancer cell and do tests to find the most effective treatment before ever administering drugs to the human patient.

Further implications of Reboredo and her colleagues’ work involve the use of a BioVaSc-type method for studying non-tumorous diseases. “In the long term we want to be able to develop disease models, especially for diseases where no animal models are available,” Reboredo said.

When asked why she and her colleagues published in JoVE, Reboredo noted that their models “can be explained and visualized best in a movie [and] to publish in such a media is made possible by JoVE.”

Source: EurekAlert!

Details of Gene Pathways Suggest Fine-Tuning Drugs for Child Brain Tumors

Pediatric researchers, investigating the biology of brain tumors in children, are finding that crucial differences in how the same gene is mutated may call for different treatments. A new study offers glimpses into how scientists will be using the ongoing flood of gene-sequencing data to customize treatments based on very specific mutations in a child’s tumor.

“By better understanding the basic biology of these tumors, such as how particular mutations in the same gene may respond differently to targeted drugs, we are moving closer to personalized medicine for children with cancer,” said the study’s first author, Angela J. Sievert, MD, MPH, an oncologist in the Cancer Center at The Children’s Hospital of Philadelphia.

Sievert, working with co-first author Shih-Shan Lang, MD, in the translational laboratory of neurosurgeon Phillip Storm, MD, and Adam Resnick, PhD, published a study ahead of print recently in the Proceedings of the National Academy of Sciences.

Studying mutation behavior in the BRAF gene in astrocytoma

The study, performed in cell cultures and animals, focused on a type of astrocytoma, the most common type of brain tumor in children. When surgeons can fully remove an astrocytoma (also called a low-grade glioma), a child can be cured. However, many astrocytomas are too widespread or in too delicate a site to be safely removed. Others may recur. So pediatric oncologists have been seeking better options—ideally, a drug that can selectively and definitively kill the tumor with low toxicity to healthy tissue.

The current study focuses on mutations in the BRAF gene, one of the most commonly mutated genes in human cancers. Because the same gene is also mutated in certain adult cancers, such as melanoma, the pediatric researchers were able to make use of recently developed drugs, BRAF inhibitors, which were already being tested with some success against melanoma in adults.
The current study provides another example of the complexity of cancer: in the same gene, different mutations behave differently. Sievert and her colleagues at Children’s Hospital were among several research groups who reported almost simultaneously in 2008 and 2009 that mutations in the BRAF gene were highly prevalent in astrocytomas in children. “These were landmark discoveries, because they suggested that if we could block the action of that mutation, we could develop a new, more effective treatment for these tumors,” said Sievert.

However, follow-up studies in animal models were initially disappointing. BRAF inhibitors that were effective in BRAF-driven adult melanomas made brain tumors worse—via an effect called paradoxical activation.

Further investigation revealed how tumor behavior depended on which type of BRAF mutation was involved. The first-generation drug that was effective in adult melanoma acted against point mutations in BRAF called V600E alterations. However, in most astrocytomas the mutation in the BRAF gene was different; it produced a fusion gene, designated KIAA1549-BRAF. When used against the fusion gene, the first-generation drug activated a cancer-driving biological pathway, the MAPK signaling cascade, and accelerated tumor growth.

Newly identified second-generation BRAF inhibitor disrupted cancer-promoting signals without adverse effects

By examining the molecular mechanisms behind drug resistance and working with the pharmaceutical industry, the current study’s investigators identified a new, experimental second-generation BRAF inhibitor that disrupted the cancer-promoting signals from the fusion gene, and did not cause the paradoxical activation in the cell cultures and animal models.

Results lay foundation for multicenter clinical trials

This preclinical work result lays a foundation for multicenter clinical trials to test the mutation-specific targeting of tumors by this class of drugs in children with astrocytomas, said Sievert. As this effort progresses, it will benefit from CHOP’s commitment to resources and collaborations that support data-intense research efforts.

The direction of brain tumor research over the past several years reflects some of those data-driven advances, says Adam C. Resnick, PhD, the senior author of the current paper and principal investigator of the astrocytoma research team in the Division of Neurosurgery at Children’s Hospital. “For years, astrocytomas have been lumped together based on similar appearance to pathologists studying their structure, cell shape and other factors,” said Resnick. “But our current discoveries show that the genetic and molecular structure of tumors provides more specific information in guiding oncologists toward customized treatments.”

Earlier this year, Children’s Hospital announced its collaboration with the gene-sequencing organization BGI-Shenzhen in performing next-generation sequencing of pediatric brain tumors at the Joint Genome Center, BGI@CHOP. The center’s sophisticated, high-throughput sequencing technology will greatly speed the discovery of specific gene alterations involved in childhood brain cancers.

This genomic discovery program dovetails with the work of the Childhood Brain Tumor Tissue Consortium, a multi-institutional collaboration recently launched by CHOP, with support from the Children’s Brain Tumor Foundation. Because even large research centers may not hold enough tumor tissue specimens to power certain research, the consortium pools samples from a group of institutions, providing an important scientific resource for cooperative studies.

“The better we understand the mutational landscape of tumors, the closer we’ll be to defining therapies tailored to a patient’s specific subtype of cancer,” added Resnick.

Study: Paradoxical activation and RAF inhibitor resistance of BRAF protein kinase fusions characterizing pediatric astrocytomas

Source: The Children’s Hospital of Philadelphia

Hopkins Scientists Create Method To Personalize Chemotherapy Drug Selection

In laboratory studies, scientists at the Johns Hopkins Kimmel Cancer Center have developed a way to personalize chemotherapy drug selection for cancer patients by using cell lines created from their own tumors. If the technique is successful in further studies, it could replace current laboratory tests to optimize drug selection that have proven technically challenging, of limited use, and slow, the researchers say.

Oncologists typically choose anticancer drugs based on the affected organs’ location and/or the appearance and activity of cancer cells when viewed under a microscope. Some companies offer commercial tests on surgically removed tumors using a small number of anticancer drugs. But Anirban Maitra, MBBS, professor of pathology and oncology at the Johns Hopkins University School of Medicine, says the tissue samples used in such tests may have been injured by anesthetic drugs or shipping to a lab, compromising test results.

By contrast, he says “our cell lines better and more accurately represent the tumors, and can be tested against any drug library in the world to see if the cancer is responsive.”

The Johns Hopkins scientists developed their test-worthy cell lines by injecting human pancreatic and ovarian tumor cells into mice genetically engineered to favor tumor growth. Once tumors grew to one centimeter in diameter in the mice, the scientists transferred the tumors to culture flasks for additional studies and tests with anticancer drugs.

In one experiment, they successfully pinpointed the two anticancer drugs from among more than 3,000 that were the most effective in killing cells in one of the pancreatic cancer cell lines. A report on the success was published online Jan. 22 in the journal Clinical Cancer Research.

The new method was designed to overcome one of the central problems of growing human tumor cell lines in a laboratory dish — namely the tendency of noncancerous cells in a tumor to overgrow cancerous ones, says James Eshleman, M.D., Ph.D., professor of pathology and oncology and associate director of the Molecular Diagnostics Laboratory at Johns Hopkins. As a consequence, it has not been possible to conventionally grow cell lines for some cancers. Still other cell lines, Eshleman says, don’t reflect the full spectrum of disease.

To solve the problem of overcrowding by noncancerous cells, Maitra and Eshleman bred genetically engineered mice that replace the noncancerous cells with mouse cells that can be destroyed by chemicals, leaving pure human tumor cells for study.

“Our technique allows us to produce cell lines where they don’t now exist, where more lines are needed, or where there is a particularly rare or biologically distinctive patient we want to study,” says Eshleman.

In its proof of concept research, the Johns Hopkins team created three pancreatic ductal adenocarcinoma cell lines and one ovarian cancer cell line. They then tested one of the pancreatic cancer cell lines (called Panc502) against the Johns Hopkins Drug Library of 3,131 drugs, identifying tumor cells most responsive to the anticancer drugs digitoxin and nogalamycin.

For 30 days, they watched the effects in living mice of the two drugs and a control medicine on tumors grown from implanted cells derived from Panc502 and an additional pancreatic cell line, Panc410. They measured the size of tumors twice a week. Both drugs demonstrated more activity in reducing the tumor appearance and size in Panc502 than in Panc410, supporting the notion that the cell line technology may better predict sensitivity to the two drugs.

The investigators have given one type of their genetically engineered mice to The Jackson Laboratory in Bar Harbor, ME, a mouse genetics research facility, for breeding and distribution to other laboratories and are looking to partner with a company to distribute two other types.

Study co-authors were Hirohiko Kamiyama, Sherri Rauenzahn, Joong Sup Shim, Collins A. Karikari, Georg Feldmann, Li Hua, Mihoko Kamiyama, F. William Schuler, Ming-Tseh Lin, Robert M. Beaty, Balasubramanyam Karanam, Hong Liang, Michael E. Mullendore, Guanglan Mo, Manuel Hidalgo, Elizabeth Jaffee, Ralph H. Hruban, Richard B. S. Roden, Antonio Jimeno, and Jun O. Liu, of Hopkins; and H. A. Jinnah of Emory University School of Medicine in Atlanta.

The work was supported by the National Institutes of Health, National Cancer Institute (CA130938, CA62924 and CA122581), the Sol Goldman Pancreatic Cancer Research Center, the Stewart Trust Fund, the Lustgarten Foundation, the Mary Lou Wootton Pancreatic Pancreatic Cancer Research Fund, the Michael Rolfe Pancreatic Cancer Foundation and the HERA Foundation.

Rauenzahn, Maitra and Eshleman may receive royalty payments if the mice are licensed, and Eshleman is an advisory board member for Roche Molecular Diagnostics. These relationships have been disclosed and are under the management of the Johns Hopkins University School of Medicine Conflict of Interest Committee.

Source: Johns Hopkins Medicine