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Liu Y.,University of Southern California | Fang J.,University of Southern California | Kim Y.-J.,University of Southern California | Wong M.K.,Norris Comprehensive Cancer Center | Wang P.,University of Southern California
Molecular Pharmaceutics

Combining chemotherapeutics is a promising method of improving cancer treatment; however, the clinical success of combination therapy is limited by the distinct pharmacokinetics of combined drugs, which leads to nonuniform distribution. In this study, we report a new robust approach to load two drugs with different hydrophilicities into a single cross-linked multilamellar liposomal vesicle (cMLV) to precisely control the drug ratio that reaches the tumor in vivo. The stability of cMLVs improves the loading efficiency and sustained release of doxorubicin (Dox) and paclitaxel (PTX), maximizing the combined therapeutic effect and minimizing the systemic toxicity. Furthermore, we show that the cMLV formulation maintains specific drug ratios in vivo for over 24 h, enabling the ratio-dependent combination synergy seen in vitro to translate to in vivo antitumor activity and giving us control over another parameter important to combination therapy. This combinatorial delivery system may provide a new strategy for synergistic delivery of multiple chemotherapeutics with a ratiometric control over encapsulated drugs to treat cancer and other diseases. © 2014 American Chemical Society. Source

Crawled News Article
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A simple blood test could have the potential to replace an invasive biopsy in breast cancer patients, according to positive results from a University of Southern California study presented Monday at The American Association for Cancer Research Annual Meeting 2016. The so called “liquid biopsy”, Parsoritx, developed by specialist medical diagnostic company Angle plc, was put through a head to head comparison of the results of the invasive metastatic biopsy by researchers at the USC Norris Comprehensive Cancer Center. For the study researchers analyzed CTCs (circulating tumor cells) collected from a simple blood test, as well as tissue from an invasive biopsy of a secondary cancer site, and found the blood test demonstrated a statistically significant correlation between the expression signature of 192 genes, with similar analysis of the tissue from the invasive procedure. Both the tissue and the CTCs were subjected to whole-transcriptome analysis using total RNA sequencing. Through this technique scientists can measure thousands of genes simultaneously to pull a fuller picture of cellular function into focus. Tissue samples were taken from numerous metastatic sites, including skin, fluid around the heart, breast, and bone tissue.  According to the company, for all of the different sites the CTCs showed a similar gene expression compared to the metastatic biopsy, suggesting that the same clinically relevant information can be attained from a blood test as from an invasive biopsy regardless of its location. Some of the main advantages to using a liquid biopsy to harvest cancer cells for analysis are that it could reduce the time it takes to make treatment decisions, and avoid delays in treatment because of recovery after an invasive procedure.  The company said this technique also enables researchers to receive information on all cancer sites at once, rather than a single site, and allows for continued assessment of tumor biology over time. “As a breast cancer surgeon, I am very enthusiastic about the potential of liquid biopsy to gain information to guide the treatment of breast cancer patients based on the specific tumor biology for each patient,” Julie E. Lang, M.D., director of USC Breast Cancer Program and associate Professor of Surgery at the Norris Comprehensive Cancer Center said in prepared statement. “Our pilot data shows that potentially the same information can be obtained from a simple blood test using Parsortix as from an invasive tissue biopsy and indeed may be advantageous over invasive tissue biopsies in regards to the diverse sites of metastatic disease, thus providing a compelling rationale for use in clinical practice after further validation.” Next, Angle plans to work with USC to run clinical studies to confirm the pilot data of using the Parsortix system as a clinical application for biopsy of metastatic breast cancer patients. Establish your company as a technology leader! For more than 50 years, the R&D 100 Awards have showcased new products of technological significance. You can join this exclusive community! Learn more.

Crawled News Article
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Researchers have developed a mathematical model to forecast metastatic breast cancer survival rates using techniques usually reserved for weather prediction, financial forecasting and surfing the Web. For decades, medical schools have taught doctors that the best way to treat cancer and metastatic progression is to memorize a list of tumors and their typical migration patterns. Metastasis is the development of malignant tumor growths elsewhere from the primary site of cancer. "This is akin to back in the days when weather reporting depended solely on a barometer and experience," said Jorge Nieva, an associate professor of clinical medicine at the Keck School of Medicine of USC and co-author of a new study. "Medical students are taught very fundamental cancer progression patterns. What the modeling does is it brings the sort of complexity of modern-day weather forecasting to trying to understand where tumors go, when they go and how they get to that location. This type of mathematical modeling is wholeheartedly different from what most medical students learn today." The study, published online October 21, 2015, in the journal npj Breast Cancer, a Nature Partner Journal, looked at 25 years of data regarding 446 breast cancer patients at Memorial Sloan Kettering Cancer Center. It focused on a subgroup of women who were diagnosed with localized disease but later relapsed with metastatic disease. The model shows that cancer metastasis is neither random nor unpredictable. Survival depends significantly on the location of the first metastatic site or "spatiotemporal patterns." In other words, USC researchers uncovered a framework to explain how tumor cells circulate through a patient's bloodstream over time to settle in various organs. The path that varies depending on tumor makeup and treatment decisions. "There's nothing like this in the cancer world; there's nothing really like this in the disease progression community even though the techniques are well-developed in other contexts," said Paul Newton, lead author of the study and an aerospace and mechanical engineering professor in the USC Viterbi School of Engineering. "Our long-term goal is to build comprehensive predictive computational simulations of metastatic cancer. Ultimately, what we want to do is tailor those models to individual patients using their individual characteristics." The framework USC researchers built combines scattered data points doctors are already collecting in order to produce an understandable, comprehensive cancer map. The system design is comparable to information Google collects to predict Web surfing patterns and to determine PageRank. "If somebody is reading about breast cancer on Wikipedia, the likelihood that she is going to jump to a lung cancer page or a bone cancer page is much higher than the likelihood of her jumping to the Costco Web site," said Newton, who is also a professor at the Norris Comprehensive Cancer Center in the Keck School of Medicine of USC as well as professor of mathematics. "These probabilities of jumping from one page to another are not all equal. Where you jump to next depends strongly on where you currently are. This observation lies at the heart of our model." Breast cancer patients die when tumors have colonized an average of four metastatic sites, the study found. Women had the poorest chances of long-term survival if they had more than two initial metastatic locations; they fared much better if migrating tumor cells first landed on one organ. Roughly 35 percent of breast cancer patients developed first metastasis to the bone, while less than five percent contracted their first metastasis in the brain, Newton said. The five-year survival of the bone group is more than 90 percent, whereas the brain group had survival characteristics of 20 percent or less, he said. Peter Kuhn, senior author of the study, explained further. "If you have breast cancer with metastasis to the bone and your next metastasis is the liver, you are likely to die from that," said Kuhn, Dean's Professor of Biological Sciences and professor of medicine, biomedical engineering, and aerospace, and mechanical engineering in the USC Dana and David Dornslife College of Letters, Arts and Sciences. "If you have breast cancer with metastasis to the bone, and the next metastasis is in the lung, you are unlikely to die from that. Instead, the disease is going to spread further first." The study's results led the researchers to further define the words "spreaders" and "sponges" to describe metastasis, a nomenclature that eventually could inform medical teams how best to deliver personalized therapy plans. "A spreader is a site that is likely the source of new disease," Kuhn said. "Hence you need to avoid spreaders or eliminate the disease if it shows up at a spreader site. At a sponge site, one might just manage or stabilize. Of course, if you could eliminate all of it, you would. But, if you have multiple metastasis, one would attempt to stabilize the sponge but eliminate the spreader." Bone, chest wall and mammary lymph nodes were spreader sites in the patients sampled. Lungs, distant lymph nodes and liver were sponge sites. The future of cancer care could be squads consisting of a biologist, a mathematician, a physicist and a computer programmer to complement the current medical teams, Newton said. USC is working on a convergent science initiative that provides a collaborative environment for cancer experts. Construction of the USC Michelson Center for Convergent Bioscience broke ground in October 2014. It will eventually be the largest building on campus. "Over the next five to 10 years, there's going to be a big change in the way medical schools and oncologists think about disease," he said. "I could easily see a situation 10 years down the road where a patient comes in with a particularly difficult disease. The oncologists in charge will put together a team of researchers to develop a model to forecast disease progression and determine best treatment options that they would then implement." Citation: Paul K Newton, Jeremy Mason, Neethi Venkatappa, Maxine S Jochelson, Brian Hurt, Jorge Nieva, Elizabeth Comen, Larry Norton, Peter Kuhn. Spatiotemporal progression of metastatic breast cancer: a Markov chain model highlighting the role of early metastatic sites. npj Breast Cancer, 2015; 1: 15018 DOI: 10.1038/npjbcancer.2015.18

Han H.,Norris Comprehensive Cancer Center | Cortez C.C.,Norris Comprehensive Cancer Center | Yang X.,Norris Comprehensive Cancer Center | Nichols P.W.,University of Southern California | And 2 more authors.
Human Molecular Genetics

Despite the fact that 45%of allhumangene promoters do not containCpGislands, the role ofDNAmethylation in control of non-CpG island promoters is controversial and its relevance in normal and pathological processes is poorly understood. Among the few studies which investigate the correlation between DNA methylation and expression of genes with non-CpG island promoters, the majority do not support the view that DNA methylation directly leads to transcription silencing of these genes. Our reporter assays and gene reactivation by 5-aza-2′-deoxycytidine, aDNAdemethylating agent, show thatDNAmethylation occurring atCpGpoorLAMB3promoter and RUNX3 promoter 1(RUNX3 P1) can directly lead to transcriptional silencing in cells competent to express these genes in vitro. Using Nucleosome Occupancy Methylome- Sequencing, NOMe-Seq, a single-molecule, high-resolution nucleosome positioning assay, we demonstrate that active, but not inactive, non-CpG island promoters display a nucleosome-depleted region (NDR) immediately upstream of the transcription start site (TSS). Furthermore, using NOMe-Seq and clonal analysis, we show that in RUNX3 expressing 623 melanoma cells, RUNX3 P1 has two distinct chromatin configurations: one is unmethylated with an NDR upstream of the TSS; another is methylated and nucleosome occupied, indicating that RUNX3 P1 is monoallelically methylated. Together, these results demonstrate that the epigenetic signatures comprising DNA methylation, histone marks and nucleosome occupancy of non-CpG island promoters are almost identical to CpG island promoters, suggesting that aberrant methylation patterns of non-CpG island promoters may also contribute to tumorigenesis and should therefore be included in analyses of cancer epigenetics. © The Author 2011. Published by Oxford University Press. All rights reserved. Source

Park S.L.,Norris Comprehensive Cancer Center | Carmella S.G.,University of Minnesota | Ming X.,University of Minnesota | Vielguth E.,University of Minnesota | And 3 more authors.
Cancer Epidemiology Biomarkers and Prevention

Background: Results of the Multiethnic Cohort (MEC) study demonstrated that, for the same quantity of cigarettes smoked, African Americans and Native Hawaiians have a higher risk of lung cancer compared with whites, whereas Latinos and Japanese Americans have a lower risk. We hypothesize that the uptake and/or metabolism of the lung carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) could explain the differences in lung cancer risk. Methods: We measured urinary 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and its glucuronides and their sum (total NNAL), biomarkers of NNK uptake, in 2,252 smokers from the MEC. Ethnic-specific geometric means were compared adjusting for age at urine collection, sex, creatinine and total nicotine equivalents, a marker of total nicotine uptake. Results: African Americans had the highest median total NNAL levels (1.80 pmol/mL urine) and Japanese Americans had the lowest (0.914 pmol/mL urine), with intermediate values in the other three groups. Geometric mean of total NNAL in African Americans was also highest, and in Japanese Americans it was lowest; Japanese American geometric mean was statistically different from whites (P = 0.004). Conclusions: African Americans had higher levels of total NNAL per mL urine than whites, while Japanese Americans had lower levels, consistent with lung cancer risk among smokers in these groups. However, our data were not consistent with the high and low lung cancer risks of Native Hawaiian and Latino smokers, respectively. Impact: The higher lung cancer susceptibility of African-American smokers and the lower susceptibility of Japanese-American smokers compared with whites can be explained in part by exposure to the potent lung carcinogen NNK. © 2014 AACR. Source

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