Triple negative breast cancer develop resistance to chemotherapy by turning on molecular

first_imgReviewed by James Ives, M.Psych. (Editor)Apr 19 2019Researchers at The University of Texas MD Anderson Cancer Center have discovered that triple negative breast cancer (TNBC) cells can develop resistance to frontline, or neoadjuvant, chemotherapy not by acquiring permanent adaptations, but rather transiently turning on molecular pathways that protect the cells.The study, published today in Science Translational Medicine, also identifies a vulnerability that may provide a new treatment option for resistant TNBC. Among those pathways activated is a metabolic process, known as oxidative phosphorylation, which can be targeted by a small-molecule drug developed by MD Anderson’s Therapeutics Discovery division.”Modern chemotherapy is highly effective for nearly half of patients with triple negative breast cancers,” said corresponding author Helen Piwnica-Worms, Ph.D., professor of Experimental Radiation Oncology. “However, the remaining half of women will not fully respond to neoadjuvant chemotherapy, and there currently are no approved treatments to improve outcomes for them. Understanding how tumor cells become resistant will allow us to identify new targets to better treat resistant disease.”According to the American Cancer Society, an estimated 268,000 women will be diagnosed with breast cancer this year, of which 15 to 20 percent will have TNBC. Standard treatment for patients with TNBC is neoadjuvant chemotherapy followed by surgery to remove the tumor. For women with tumors that don’t fully respond to chemotherapy, there is a much higher risk of recurrence and death from the disease, said Piwnica-Worms.In order to study how TNBC cells become resistant to treatment, the researchers created mouse models, known as patient-derived xenografts (PDXs), of TNBC using tumor samples from patients enrolled in the ARTEMIS clinical trial, led by MD Anderson’s Breast Cancer Moon Shot™.Patients enrolling in ARTEMIS have tumor biopsies taken before and after neoadjuvant chemotherapy treatment, which enable researchers to study why some tumors are resistant and discover more effective strategies to bring cures to more patients. The work is part of MD Anderson’s Moon Shots Program™, a collaborative effort designed to accelerate the development of scientific discoveries into clinical advances that save patients’ lives.Related StoriesAI-enabled device detects if targeted chemotherapy is workingRutgers researchers create new device to see if targeted cancer therapy is workingScientists discover how resistance to the chemotherapy drug 5-fluorouracil arisesPiwnica-Worms’ team identified several PDX models that responded to chemotherapy at first, but eventually developed resistance and resumed tumor growth. If treatment was paused, however, the residual tumors once again became sensitive to chemotherapy, indicating the resistance was temporary.Under the microscope, tumors showed distinct changes during treatment, but regrown tumors appeared similar to those before treatment. Further, an analysis of individual tumor cells showed that the heterogeneity of cells in a given tumor was maintained after treatment, suggesting that chemotherapy did not select for a small subset of resistant cells.Characterization of gene expression changes revealed a set of pathways activated as part of the resistant state, which were turned off when chemotherapy was discontinued. The researchers confirmed many of these molecular changes were mirrored in biopsies taken from ARTEMIS patients.Hoping to find new treatment targets for resistant TNBC, the researchers discovered that these cells had become dependent on oxidative phosphorylation for energy production. This pathway is the target of IACS-10759, the first-small molecular discovered and developed by MD Anderson’s Therapeutics Discovery division.When treating the PDX mice with IACS-10759 following chemotherapy treatment, the researchers observed a synergistic effect, suggesting sequential treatment of chemotherapy and IACS-10759 could prolong the duration of treatment response. IACS-10579 is now in clinical trials for a variety of hematological and solid cancer types.”Our study provides a compelling rationale for defining additional properties that enable triple negative breast cancers to survive chemotherapy treatment, so that combination therapies can be developed to eradicate this disease,” says Piwnica-Worms. “A long-term goal is to avoid the use of chemotherapy in patients with resistant disease and instead employ targeted therapies to avoid unnecessary treatments and harsh side effects.”Source: read more

Researchers map drink consumption around the world

first_imgBy Dr. Ananya Mandal, MDJun 9 2019Researchers, in one of the most comprehensive global studies, have mapped the type and quantities of drinks consumed around the world. They explain that a major portion of the daily calorie and nutrition intake comes from the beverages consumed. The results of the study were presented at Nutrition 2019, the American Society for Nutrition annual meeting, held June 8-11, 2019 in Baltimore. In their study the team looked at beverage consumption habits from 185 countries around the world. Lead study author Laura Lara-Castor, a doctoral student in the Friedman School of Nutrition Science and Policy at Tufts University spoke about her “Global Dietary Database project,” saying that, “These preliminary data derived from the Global Dietary Database project can help inform nutrition transitions over time, the impacts of these beverages on global health, and targeted dietary policy to improve diet and health.”The team looked at 2015 data by compiling results from 1,100 surveys that were taken by 6.78 billion people around the world. The surveys looked at various dietary and beverage consuming habits.According to Lara-Castor and her team some patterns emerged from their study. She said, “Notably, sugar-sweetened beverage and fruit juice intake was highest in the Latin American region, where both commercial and homemade sugar-sweetened beverages and fruit drinks are widely consumed. Milk intake was highest in the high-income region (including countries such as Sweden, Iceland and Finland) where dairy farming is more widespread and dairy consumption has been traditionally a major part of the diet.” Youngsters living in urban areas and those with higher education levels consumed more beverages than otherwise, the team noted. Milk intake was high among those below 12 years of age as well as those above 72 years of age, found the study.Results revealed that in Mexico, sugar-sweetened beverage consumption was at its highest with an average adult consuming over 19 ounces or 2.5 cups per day. Suriname and Jamaica came next with an average of around 15 ounces per day. China, Indonesia and Burkina Faso showed lowest consumption of these beverages. Fruit juice consumption was highest in nations such as Colombia and the Dominican Republic at around 10 to 11 or 1.4 cups per day. China, Portugal and Japan consumed lowest amounts of fruit juices, the team noted. Nations such as Sweden, Iceland and Finland consumed more milk than other nations at 9 or 10 ounces or 1.3 cups per day average. China, Togo and Sudan consumed least amount of milk on an average.Related StoriesHealthy high-fiber diet could reduce preeclampsia riskDiet and nutrition influence microbiome in colonic mucosaJAMA commentary: Nutrition knowledge essential for today’s physiciansThe researchers explain that Mexico with its highest consumption of sugary beverages is also a place where rates of obesity are one of the highest. Reports show that over 70 percent of the population in the nation is overweight or obese and over 70 percent of their sugar consumption comes from these sugary beverages with Coca-Cola being the most favourite. To curb use, the Mexican government has added sugar taxes. After the first year of this taxing there has been a 5.5 percent drop in sugar consumption of the nation. In the second year after the taxes were in place, there was a 9.7 percent drop in sugar consumption. This study also noted that sugary drink consumption as well a s fruit juice consumption was high not only for commercially available packaged drinks but also home-made sugary drinks.According to Lara-Castor, “For sugar-sweetened beverages, fruit juice and milk, these data reflect updated and expanded estimates of the 2010 GDD, while for coffee and tea these constitute the first global quantitative estimates to be ever reported.” She said, “These data highlight gaps in dietary surveillance, further helping inform nutrition transitions over time, the impacts of these beverages on global health, and targeted dietary policy to improve diet and health.”The team adds that there were some limitations in the study. They write that the beverage consumption data came for only certain beverages, within a certain time period in the country. Lara-Castor said, “In particular, more intake data were available in 2015 than in 1990, and relatively few intake data were available in most Sub-Saharan African nations. [Nevertheless,] our findings represent the best available, yet still imperfect, data on global intakes of key foods.” She explained, “In ongoing work, we are updating our searches, data collection and modelling, to overcome each of these prior limitations.”Overall the study gives a fair idea of what the world is drinking, said Lara-Castor. This may help develop nutritional policies that could be beneficial to public health she concluded. Paket / Shutterstocklast_img read more

New protein target for deadly ovarian cancer

first_imgThe good news about the newly discovered protein is that it can be inhibited, thus inactivating cell processes within ovarian cancer cells to switch them from a constitutively proliferative cell cycle to one which results in senescence, or going to sleep. The key role of the protein was identified on cell culture experiments by researchers at Penn State College of Medicine.The current study focused on teasing out the differences in the metabolism of ovarian cancer cells by comparing them with cells from a normal fallopian tube.The route used to achieve this was quantitative spectrometry, which helped analyze the metabolites produced by various cellular pathways in the two type of tissue. Among the differences, it was revealed that cancer cells utilized glucose, a form of sugar, via the key energy cycle called the citric acid cycle, far more often, as against the more common use of an oxygen-requiring pathway called aerobic glycolysis. This accounts for the presence of a high level of citric acid activity in all high-grade serous ovarian cancer cells.  Related StoriesLiving with advanced breast cancerUsing machine learning algorithm to accurately diagnose breast cancerMother calls for protein shake regulation after daughter diesThis means that many therapies which inhibit the breakdown of glucose (glycolysis) to destroy cancer cells may be quite ineffective. Dahl commented that this could often result, in fact, in the production of toxins that harm normal healthy tissue.Instead, the team in the current study looked at the effects of inhibiting the wildtype or normal form of an enzyme, isocitrate dehydrogenase 1 (IDH 1), which plays a vital part in the citric acid cycle. They selected this protein because it was the only one in this pathway that is expressed at higher levels in both adherent and spheroid tumor cells. Increased activity of this enzyme severely impacts progression-free survival, which is an important outcome measured in assessing the effectiveness of any cancer therapy.Mutants of this protein are common in other tumors, but the wildtype form is typically present in cells within HGSC. The researchers hypothesize that the presence of this enzyme is an important advantage to these cells, and its inhibition is a key step to inducing senescence.The researchers found that suppressing the work of this protein stopped cell division completely by suppressing the activity of multiple other genes, inhibiting vital metabolic pathways. Both adherent cells of the primary tumor, and spheroid cells of secondary HGSC, become senescent when the wildtype IDH 1 enzyme is inhibited. Thus, this could be an excellent way to treat HGSC at all stages. This is an important consideration, as ovarian cancers are rarely diagnosed at early stages.While there are already FDA (US Food and Drug Administration)-approved drugs against one of the mutant forms of this enzyme, the team wondered whether they would work against the wildtype form as well. They found that one did, and this is now a part of their continued research agenda.Aird says, “One of our long-term goals is to try and repurpose this already-approved drug as a treatment for this form of ovarian cancer.” Besides adapting existing drugs against the enzyme to fight this type of cancer, the researchers want to examine the differences in the metabolic functioning of normal and HGSC cells more closely. Another goal is to examine the effectiveness of combining IDH 1 inhibitors with other treatments. Journal reference:Targeting IDH1 as a Prosenescent Therapy in High-grade Serous Ovarian Cancer, Erika S. Dahl, Raquel Buj, Kelly E. Leon, Jordan M. Newell, Yuka Imamura, Benjamin G. Bitler, Nathaniel W. Snyder and Katherine M. Aird, Mol Cancer Res June 17 2019 DOI: 10.1158/1541-7786.MCR-18-1233, By Dr. Liji Thomas, MDJul 14 2019A new study shows that targeting a specific protein found within quickly spreading high-grade serous carcinomas (HGSC) of the ovary could help contain these cancers. HGSC is the most common and deadly form of epithelial ovarian cancer, which is itself the deadliest cancer of the female reproductive tract. When HGSC spreads outside the ovaries, within the peritoneal cavity, it forms detached balls called spheroids, which may look and act differently from the adherent cells of the primary tumor.The study is published in the current issue of the journal Molecular Cancer Research. However, as researcher Erika Dahl explains, “A hallmark of cancer cells is that their metabolic processes are often different from normal, healthy cells.”  This is called metabolic reprogramming. As one of the outcomes, study author Katherine Aird says, “Cancer cells can grow forever without stimulus.” 70% of HGSC relapse despite treatment, becoming resistant to chemotherapy, which makes the new discovery a true potential breakthrough in the treatment of this tumor.All life at cellular and organism level depends upon thousands of life processes that provide and degrade a range of chemicals required for proper function of the cells and tissues. These intricately interdependent processes together they make up the body’s metabolism. Cancer cell Illustration. Image Credit: Jovan Vitanovski / Shutterstocklast_img read more

KCR sets high growth agenda as Telangana celebrates State formation day

first_imgCOMMENTS Telangana Chief Minister K Chandrasekhar Rao called upon the people to strengthen the Government weeding out corruption in administration and take the state into high growth path.Addressing the fifth anniversary celebrations of the Telangana formation, the Chief Minister mentioned about three legislations for municipal, panchayat raj, and revenue administration and said they were aimed at making them corruption free.The celebrations were relatively a low key fair due to the election code and oppressive summer.He said “By giving equal importance to development and welfare we initiated a process of reconstruction of the State.”Telangana, he said, has emerged as a powerful force stabilising itself as a state on progress. “Our State registered on an average 16.5 per cent revenue growth during the past five years. If the same trend continues, the indications clearly show that the State’s revenue will witness a multiplier growth. To further expand the development this growth rate augurs well.”Rao said, “We were able to demonstrate during the past five years some permanent solutions to several critical problems during the past five decades. This includes surmounting the power crisis, enabling 24×7 power to all sectors including agriculture. This has rejuvenated both the agriculture and industrial sectors.”Referring to the Mission Bhagiratha, which seeks to address the drinking water problem, he said it is at an advanced stage of completion in almost all rural areas. It will be commissioned on July 1.Mentioning about various welfare schemes, he said that their benefits will have far reaching impact on the people in the years to come.Referring to the irrigation projects his Government had taken up, including the mega Kaleshwaram lift irrigation project, the Chief Minister said “once these irrigation projects are completed, the entire Telangana will have green fields. This will ensure State becomes drought free and there will be water throughout the year.”On the Investment Support scheme for agriculture under the Rythu Bandhu, he said “We ensure that the farmer does not get into debts by giving Rs 4,000 per acre, per crop totalling Rs 8000 for two crops.” He announced enhancement of the amount to Rs 5,000 per acre per season working out to Rs 10,000 for two seasons per acre. K Chandrasekhara Rao (file photo).   –  The Hindu June 02, 2019 COMMENT Published on SHARE SHARE SHARE EMAIL Telanganalast_img read more