Sorafenib Stops Tumor Growth And Provides The First Effective Treatment For Thyroid Cancer Patients Who Progress Following Standard Therapies

Main Category: Cancer / Oncology
Also Included In: Endocrinology;??Ear, Nose and Throat
Article Date: 04 Jun 2013 - 0:00 PDT Current ratings for:
Sorafenib Stops Tumor Growth And Provides The First Effective Treatment For Thyroid Cancer Patients Who Progress Following Standard Therapies

The kidney and liver cancer drug sorafenib holds metastatic thyroid cancer at bay for nearly twice as long as a placebo, according to results of a randomized phase III trial, which was presented by a researcher from the Abramson Cancer Center and the Perelman School of Medicine at the University of Pennsylvania in a plenary session during the American Society of Clinical Oncology's annual meeting (Abstract #4).

If approved for use in thyroid cancer patients by the Food and Drug Administration, sorafenib (Nexavar), a kinase inhibitor that mediates tumor cell division and growth of tumor blood vessels, would be the first effective agent for this patient population. Thyroid cancer is highly curable through surgery and radioactive iodine treatment, but about 10 percent of the 60,000 patients who are diagnosed with the disease each year fail to respond to standard therapies, with tumors eventually appearing in the lymph nodes, bones, lungs, and other sites. The only other drug for advanced thyroid cancer, doxorubicin, which was approved in 1974, is not used because it is highly toxic and is not effective.

"Until we began using sorafenib, we had no medical options for these patients who suffered due to progression of their disease," said Marcia S. Brose, MD, PhD, an assistant professor of Otolaryngology and Head and Neck Surgery and Hematology/Oncology, who led the study, which is known as DECISION. "Now, we can give patients hope - a breakthrough medication that can stop the progression of the disease for 5 months. This trial is the first step in a promising series of clinical trials to identify new drugs that are shifting the horizon for patients with advanced thyroid cancer."

Of the 417 metastatic thyroid cancer patients studied in the multicenter, international trial, 207 were randomized to take sorafenib, an oral drug, and 210 to a placebo arm. Twelve percent of patients experienced tumor shrinkage in the sorafenib arm, compared to 0.5 percent of patients taking a placebo. Importantly, the therapy also appeared to thwart disease progression even among many of those whose tumors did not regress: 42 patients who took sorafenib had stable disease after six months, compared to 33 percent of those in the placebo group.

Among patients taking sorafenib, median progression-free survival was 10.8 months, compared to 5.8 months among the placebo group. Patients taking the placebo were allowed to cross over into the sorafenib arm once their disease progressed; 70 percent of them did so. Overall survival data is not yet available.

The most common adverse events observed among patients taking sorafenib included hand-foot skin reaction, diarrhea, alopecia, rash, fatigue, weight loss and hypertension, all of which are consistent with findings from previous trials of the drug for its approved indications.

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our cancer / oncology section for the latest news on this subject. Bayer HealthCare Pharmaceuticals and Onyx Pharmaceuticals provided funding for the trial. Editor's note: Dr. Brose has received consulting fees and honoraria from these companies.
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Researchers reveal new potential means to suppress tumor growth

Main category: Cancer / Oncology
Also included in: genetics
Article Date: June 5, 2013-0:00 PDT current ratings for:
Researchers reveal new potential means to suppress tumor growth

Researchers at the University of California, San Diego School of Medicine, with colleagues at the University of Rochester Medical Center have identified a new mechanism that seems to remove the tumor growth, opening up the possibility of developing a new class of anti-cancer drugs.

Written in first editions online this week by the proceedings of the Academy national of Sciences (PNAS), Willis X. Li, Ph.d., Professor in the Department of medicine at UC San Diego, reports that a particular form of signaling called STAT5A protein stabilizes the formation of heterochromatin (a form of chromosomal DNA), which in turn removes the ability of cancer cells to give instructions to multiply and grow.

Specifically, Li and his colleagues concluded that the place of STAT form promotes and stabilizes the heterochromatin, which keeps DNA closely packed and inaccessible to transcription factors. "As a result, genes 'buried' in heterochromatin are not expressed," said Li.

Phosphorylation is a fundamental cellular function in which a phosphate group is added to a protein or molecule, the cause to activate or disable or modify its function. A STAT place lack of this phosphate group.

Li said that in previous studies with the fruit flies, the place of STAT caused chromatin form to condense in heterochromatin, while the phosphorylated version prompted the dispersal and loss of the heterochromatin, promoting the expression of genes.

"STAT site promotes and stabilizes the formation of heterochromatin, which in turn removes the gene transcription," Li said. "when we have expressed either HP1 (the central element of the heterochromatin) or place STAT5A in human cancer cells, several genes important for the growth of the cancer are removed." These cancer cells do not grow as fast or as large as their cancer cells parental control in xenograft models mouse."

Most suppressors tumor known, such as p53 or Rb function by inhibiting the progression of the cell cycle or by stimulating cell death or apoptosis. Li said their findings indicate a potential new way to inhibit the expression of the genes of cancer and could constitute a new class of tumour suppressors.

"We are trying to identify drugs to small molecules that can promote the formation of heterochromatin without stopping cell division or causing the death of the cell," he said. "These drugs, if found, may be effective in treating cancer with fewer side effects."

Article adapted by Medical News Today press release original. Click on "references" tab above for the source.
Visit our cancer / Oncology section for the latest news on this subject. Co-authors are Xiaoyu Hu, Amy Tsurumi and Hartmut Land, Department of biomedical genetics, University of Rochester Medical Center; Pranabananda Dutta, Jinghong Li and Jingtong Wang, Department of medicine, UCSD.
Funding of this research came, in part, grants from the National Institutes of Health R01CA131326 and RO1CA138249 and a leukemia & Lymphoma Society Research Scholar grant.
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Splicing Process Hijacked By Oncogene Mutation To Promote Growth And Survival

Main Category: Cancer / Oncology
Also Included In: Genetics
Article Date: 04 Jun 2013 - 1:00 PDT Current ratings for:
Splicing Process Hijacked By Oncogene Mutation To Promote Growth And Survival

An international team of researchers - led by principal investigator Paul S. Mischel, MD, a member of the Ludwig Institute for Cancer Research and professor in the Department of Pathology at the University of California, San Diego School of Medicine - has found that a singular gene mutation helps brain cancer cells to not just survive, but grow tumors rapidly by altering the splicing of genes that control cellular metabolism.

The findings are published online in the journal Cell Metabolism.

Mischel, who heads the Ludwig Institute's molecular pathology laboratory based at UC San Diego, and colleagues focused upon a process called alternative splicing, in which a single gene encodes for multiple proteins by including or excluding different, specific regions of DNA.

Alternative splicing is a tightly regulated and normal activity in healthy cells. For Mischel and colleagues in Los Angeles, Ohio and Japan, the question was whether mutations of a gene called EGFRvIII caused differential alternative splicing in glioblastoma multiformes (GBMs), the most common and aggressive type of malignant brain tumor. Median survival after GBM diagnosis is just 15 months with standard-of care radiation and chemotherapy. Without treatment, it is less than five months.

The scientists were particularly interested in whether the EGFRvIII mutation induced alternative splicing events that resulted in deregulation of normal cellular metabolism. "We focused on the 'Warburg Effect,' a common metabolic derangement in cancer that enables tumor cells to metabolize glucose in a way that provides both a sufficient supply of energy and a source of building blocks that can be used for growth," Mischel said.

They discovered a complex but compelling series of consequential events: The EGFRvIII mutation controls expression of a splicing factor called HNRNPA1, which initiates an alternatively spliced form of a regulatory protein called Max. The alternative form is called Delta Max.

Max is associated with MYC, a gene that drives tumor growth and the Warburg Effect in cancer. "Unlike the regular form of Max," said Mischel, "Delta Max actually enhances c-MYC activity, specifically by promoting the glycolytic phenotype of the tumor cells." In other words, the EGFRvIII mutation and subsequent alternative splicing commandeer the cell's metabolic machinery in a way that lets it take up and use glucose to promote rapid tumor growth.

Mischel noted that the findings are specific to the EGFRvIII mutation and GBMs. It's not known whether other oncogenes are able to exploit alternative splicing in similar fashion.

The findings, according to Mischel, provide two clear insights. First, they highlight the central role of EGFRvIII in GBM pathogenesis and its critical role in altering cellular metabolism in tumors. Second, they show that oncogenes can regulate cell metabolism through alternative splicing, which may provide a new set of targets for oncogene-specific drug development.

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our cancer / oncology section for the latest news on this subject. Co-authors are Ivan Babic, Kenta Masui and Beatrice Gini, Ludwig Institute for Cancer Research, UCSD; Erik S. Anderson, Department of Microbiology, Immunology and Molecular Genetics, UCLA; Kazuhiro Tanaka, Department of Neurosurgery, Kobe University, Japan; Deliang Guo, Department of Radiation Oncology, Ohio State University Medical Center; Bing Li and Siavash K. Kurdistani, Department of Biological Chemistry, UCLA; Shaojun Zhu, David Nathanson and Rui Li, Carolina Espindola Camacho and Heather R. Christofk, Department of Molecular and Medical Pharmacology, UCLA; Yuchao Gu, Ludwig Institute for Cancer Research, UCSD and Department of Molecular and Medical Pharmacology, UCLA; Genaro R. Villa, Ludwig Institute for Cancer Research, UCSD and Department of Molecular and Medical Pharmacology, UCLA; David Akhavan, Department of Molecular and Medical Pharmacology, UCLA; Sergey Mareninov, Department of Pathology and Laboratory Medicine, UCLA; Ascia Eskin and Stanley F. Nelson, Department of Human genetics, David Geffen School of Medicine, UCLA; William H. Yong, Department of Pathology and Laboratory Medicine, UCLA; Webster K. Cavenee, Ludwig Institute for Cancer Research, UCSD and UCSD Moores Cancer Center; Timothy F. Cloughesy, Department of Neurology, David Geffen School of Medicine, UCLA; and Douglas L. Black, Howard Hughes Medical Institute and Department of Microbiology, Immunology and Molecular Genetics, UCLA.

Funding for this research came, in part, from National Institutes of Health grants CA119347, NS73831, R01 GM084317 and P01 CA95616, the Ben and Catherine Ivy Foundation, Art of the Brain Fund, Accelerate brain Cancer Cure, the Fred Miller Family, the John W. Carson Foundation, the Ziering Family Foundation, the Henry Singleton Brain Cancer Fund and National Cancer Institute grant P30CA23100.

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Epidermal Growth Factor Receptor (EGFR) Levels Significantly Elevated in Women Who Developed Breast Cancer

Blood levels of epidermal growth factor receptor (EGFR) may be elevated in women up to 17 months prior to a diagnosis of breast cancer. These findings were recently presented at the American Association for Cancer Research 101st Annual Meeting.[1]?

In an attempt to improve survival by detecting breast cancer at an earlier stage, researchers are evaluating potential biomarkers of the disease. Levels of certain proteins in the blood, for example, may be higher in women with breast cancer than in women without breast cancer. If these markers reliably distinguish women with and without breast cancer, and if the markers can be identified early in cancer development (before the cancer would typically be diagnosed clinically), then they may contribute to the early detection of breast cancer.

In the current study, researchers first evaluated blood samples from 420 women with estrogen receptor-positive breast cancer and a set of matched controls (women without breast cancer). For the women with breast cancer, blood had been collected up to 17 months prior to cancer diagnosis. Biomarkers that appeared promising at this first stage (that appeared to distinguish women with and without breast cancer) were then further evaluated in a separate set of women with and without breast cancer.

EGFR levels were significantly elevated in women who developed breast cancer compared with controls. Women with the highest levels of EGFR had a 2.9-fold increased risk of developing breast cancer compared with women with the lowest EGFR levels. In women who used estrogen plus progestin hormone therapy, high EGFR levels were associated with a ninefold increased risk of developing breast cancer.

Although the results of this study did not indicate that EGFR levels were sufficient to be used as a sole predictor of breast cancer, the researchers were optimistic that “there may indeed be detectable changes of proteins in blood within two years of making a clinical breast cancer diagnosis.” This type of research continues to hold promise. ??

Reference:

[1] Pitteri SJ, Amon LM, Buson TB, et al. Elevated plasma levels of epidermal growth factor receptor prior to diagnosis of breast cancer in preclinical specimens from the Women’s Health Initiative Observational Study. Proceedings from the 101st Annual Meeting of the American Association for Cancer Research. April 17-21, 2010. Abstract 4815.

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