News Article | May 1, 2017
IMAGE: Ovarian cancer tumors with higher percentages of cIAP-expressing cells, shown in red at left, were more sensitive to a potential combination therapy than tumor cells without cIAP-expressing cells. view more Researchers have been trying to understand why up to 85 percent of women experience recurrence of high-grade serous ovarian cancer -- the most common subtype of ovarian cancer -- after standard treatment with the chemotherapy drug carboplatin. Preclinical research from Dr. Sanaz Memarzadeh, who is a member of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA, has potentially solved this mystery and pinpointed a combination therapy that may be effective for up to 50 percent of women with ovarian cancer. Memarzadeh's research, published in the journal Precision Oncology, shows a new combination therapy of carboplatin and an experimental drug called birinapant can improve survival in mice with ovarian cancer tumors. Additional findings reveal that testing for a specific protein could identify ovarian tumors for which the treatment could be effective. Importantly, the treatment could also target cancers that affect other parts of the body, including the bladder, cervix, colon and lung cancer. In 2015, Memarzadeh and her team uncovered and isolated carboplatin-resistant ovarian cancer stem cells. These cells have high levels of proteins called cIAPs, which prevent cell death after chemotherapy. Since the cancer stem cells survive carboplatin treatment, they regenerate the tumor; with each recurrence of ovarian cancer, treatment options become more limited. Memarzadeh showed that birinapant, which degrades cIAPs, can make carboplatin more effective against some ovarian cancer tumors. "I've been treating women with ovarian cancer for about two decades and have seen firsthand that ovarian cancer treatment options are not always as effective as they should be," said Memarzadeh, director of the G.O. Discovery Lab and member of the UCLA Jonsson Comprehensive Cancer Center. "Our previous research was promising, but we still had questions about what percentage of tumors could be targeted with the birinapant and carboplatin combination therapy, and whether this combination could improve overall survival by eradicating chemotherapy-resistant ovarian cancer tumors." In this new study, the research team first tested whether the combination therapy could improve survival in mice. Half of the mice tested had carboplatin-resistant human ovarian cancer tumors and the other half had carboplatin-sensitive tumors. The team administered birinapant or carboplatin as well as the two drugs combined and then monitored the mice over time. While birinapant or carboplatin alone had minimal effect, the combination therapy doubled overall survival in half of the mice regardless of whether they had carboplatin-resistant or carboplatin-sensitive tumors. "Our results suggest that the treatment is applicable in some, but not all, tumors," said Rachel Fujikawa, a fourth year undergraduate student in Memarzadeh's lab and co-first author of the study. To assess the combination therapy's rate of effectiveness in tumors, the team went on to test 23 high-grade serous ovarian cancer tumors from independent patients. Some were from patients who had never been treated with carboplatin and some were from patients who had carboplatin-resistant cancer. With these samples, the researchers generated ovarian cancer tumors utilizing a method called disease-in-a-dish modeling and tested the same treatments previously tested in mice. Once again, carboplatin or birinapant alone had some effect, while the combination of birinapant and carboplatin successfully eliminated the ovarian cancer tumors in approximately 50 percent of samples. Importantly, the combination therapy worked for both carboplatin-resistant and carboplatin-sensitive tumors. The researchers also measured cIAPs (the target for the drug birinapant) in the tumors. They found a strong correlation between cancer stem cells with high levels of cIAP and a positive response to the combination therapy. Since elevated levels of cIAPs have been linked to chemotherapy resistance in other cancers, the researchers wondered if the combination therapy could effectively target those cancers as well. The team created disease-in-a-dish models using human bladder, cervix, colon and lung cancer cells and tested the combination therapy. Similar to the ovarian cancer findings, 50 percent of the tumors were effectively targeted and high cIAP levels correlated with a positive response to the combination therapy. "I believe that our research potentially points to a new treatment option. In the near future, I hope to initiate a phase 1/2 clinical trial for women with ovarian cancer tumors predicted to benefit from this combination therapy," said Memarzadeh, gynecologic oncology surgeon and professor at the David Geffen School of Medicine at UCLA. The research was supported by an American Cancer Society Research Scholar Grant (RSG-14-217-407 01-TBG), the Phase One Foundation, the Ovarian Cancer Circle Inspired by Robin Babbini, a STOP Cancer Margot Lansing Memorial Seed award, the National Institutes of Health (R01CA183877 and #U54 MD007598) and the UCLA Broad Stem Cell Research Center.
News Article | December 13, 2016
A team of UCLA bioengineers has demonstrated that its technology may go a long way toward overcoming the challenges of treatment for acute lymphoblastic leukemia, among the most common types of cancer in children, and has the potential to help doctors personalize drug doses. The five-year survival rate for individuals with pediatric acute lymphoblastic leukemia is about 85 percent, however those who experience a recurrence generally have a poor prognosis and a bone marrow transplant is their only option for a permanent cure. Conventional treatment for this leukemia includes a combination of drugs, which come with short- and long-term side effects. Two of these drugs, 6-mercaptopurine and methotrexate, can cause liver disease and other life-threatening infections. During the maintenance phase of treatment, which aims to keep individuals in remission, dosing for these two drugs is frequently adjusted through a system of trial and error, which is not always accurate. The UCLA team from the Schools of Dentistry, Medicine and Engineering showed that its digital health technology platform, called Phenotypic Personalized Medicine, or PPM, can surmount the treatment challenges for this leukemia. The technology platform is based on the team's stunning discovery that a patient's physical response to drug treatment, such as tumor size or bacterial and viral levels in the blood, could be visually represented in the shape of a parabola, or U-shaped line. The graphs plot the drug dose along the horizontal axis and the patient's response to treatment on the vertical axis. The technology has the ability to accurately identify a person's optimal drug and dose combinations throughout an entire course of treatment. In addition, the technology platform does not require any complex and expensive analysis of a patient's genetic information or the biological basis of the disease, greatly accelerating the ability to optimize and personalize care. The team's findings appear online in the peer-reviewed journal SLAS Technology, which features innovations in technology for drug development and diagnostics. "Phenotypic Personalized Medicine is like turbocharged artificial intelligence. It personalizes combination therapy to optimize efficacy and safety," said Dean Ho, co-corresponding author of the study and professor of oral biology and medicine. "The ability for our technology to continuously pinpoint the proper dosages of multiple drugs from such a large pool of possible combinations overcomes a challenge that is substantially more difficult than finding a needle in a haystack," added Ho, who is also the co-director of the Weintraub Center for Reconstructive Biotechnology at the UCLA School of Dentistry. In this study, patient records were obtained on the dosing of 6-mercaptopurine and methotrexate, as well as on the corresponding absolute neutrophil count, or levels of a subset of white blood cells called neutrophils that are vital for staving off potentially life-threatening infections. These records showed multiple instances where conventional chemotherapy doses caused deviations from acceptable neutrophil levels. Using the personalized medicine technology, individualized three-dimensional maps were generated to determine the optimal 6-mercaptopurine/methotrexate drug ratios. The team members found that their technology-suggested drug dosages were as much as 40 percent lower compared to clinical chemotherapy dosages, while still maintaining target neutrophil levels. The parabolas showed that markedly different dosages of each drug were required to maintain normal white blood cell counts for each patient. Their results demonstrated a clear need to personalize acute lymphoblastic leukemia treatment, and will serve as a foundation for a pending clinical trial to optimize multi-drug chemotherapy. "PPM has the ability to personalize combination therapy for a wide spectrum of diseases, making it a broadly applicable technology," said Chih-Ming Ho, distinguished research professor of mechanical and aerospace engineering and co-corresponding author of the study. "The fact that we don't need any information pertaining to a disease's biological process in order to optimize and personalize treatment is a revolutionary advance. We're at the interface of digital health and cancer treatment." Dr. Vivian Chang, co-first author of the study and assistant professor of pediatrics and hematology and oncology, said, "Optimizing combination therapy for [pediatric leukemia] on a patient-specific level would be a game-changer for the way that this cancer, as well as many other cancers, is addressed. Reducing side effects while maintaining or even enhancing efficacy could also improve the long-term treatment outcomes of our patients." Chang is also co-director of the Pediatric Cancer Predisposition Clinic at UCLA. The research team is planning to recruit patients for a prospective trial within the next year. The technology is approved for additional infectious disease and oncology studies. Other authors of the study, all from UCLA, are co-first author and postdoctoral researcher Dong-Keun Lee and graduate student Theodore Kee. Dean Ho, Chih-Ming Ho and Chang are also members of the Jonsson Comprehensive Cancer Center. This work was supported by the National Cancer Institute, National Science Foundation, V Foundation for Cancer Research, Wallace H. Coulter Foundation, Society for Laboratory Automation and Screening, UCLA Children's Discovery and Innovation Institute, Today's and Tomorrow's Children Fund Award and the endowment fund of the Ben Rich-Lockheed Martin Professorship.
News Article | March 4, 2016
The overall five-year survival rate for people with pancreatic cancer is just 6 percent, and there is an urgent need for new treatment options. More than 80 percent of pancreatic cancer diagnoses occur too late for surgery, making chemotherapy the only possible treatment. Scientists from the California NanoSystems Institute at UCLA and UCLA’s Jonsson Comprehensive Cancer Center have developed a delivery system for one chemotherapy drug that greatly reduces the occurrence of serious side effects while enhancing the drug’s effectiveness against pancreatic cancer. The approach uses mesoporous silica nanoparticles to deliver the drug directly to the tumor instead of having the free drug spread throughout the body via the bloodstream. The study was led by Dr. Andre Nel, associate director of the California NanoSystems Institute, and Huan Meng, an assistant professor of nanomedicine; it was published in the journal ACS Nano. Xiangsheng Liu, a postdoctoral scholar in the UC Center for Environmental Implications of Nanotechnology, was the study’s first author. In recent years, the chemotherapy regimen known as FOLFORINOX, which combines the drugs 5-fluorouracil, irinotecan, oxaliplatin, and leucovorin, has improved survival outcomes over the standard treatment option, gemcitabine, which has fewer side effects. The severe side effects of FOLFORINOX, which are primarily caused by the irinotecan component, mean that only a minority of the healthiest patients can be treated with it. The silica nanoparticles used in the study work like glass bubbles that contain a large amount of irinotecan in pores on their surfaces. The particles are wrapped in a double layer of lipids, similar to cell membranes, which safely trap the drug without leakage until the nanoparticle reaches the cancer site, where it is designed to unload the drug based on the acidic environment of the cancer cell. “Because of stable drug retention by the lipid layers, the nanoparticles greatly reduce the amount of healthy tissue cells exposed to irinotecan,” Nel says. “The severe side effects of irinotecan largely result from its exposure to healthy tissues such as bone marrow, liver, and gut.” The researchers compared the effectiveness of the lipid-coated nanoparticles to an FDA-approved irinotecan carrier that encases drug molecules in fatty spherical particles called liposomes. In mice with human pancreatic tumors, delivering the drug via silica nanoparticles reduced tumor size more effectively than delivering it via liposomes. The nanoparticle technique was also safer because less of the drug leaked into the bloodstream. “This dramatically decreased the amount of severe side effects to the bone marrow, gastrointestinal tract and liver in the mice. The nanoparticles were also more efficient than the liposomes in treating the spread of tumors to surrounding organs,” Liu says. The researchers believe that a FOLFORINOX regimen could be made safer and more effective against pancreatic cancer using the mesoporous silica nanoparticle delivery system for irinotecan, Meng said. He added that they still have some distance to go before launching a human clinical trial, but with this study they have developed a normal strategy for irinotecan delivery by a nanoparticle. Their technique would make it relatively easy to scale up the technology to production levels, because the nanoparticles’ effectiveness means that less of the drug is required for treatment. The researchers also found that their approach can be used to deliver several other chemotherapy drugs, meaning that it may also prove useful in treating other types of cancer. Support for this research was provided by the U.S. Public Health Service and the Hirschberg Foundation for Pancreatic Cancer Research. The research utilized the Core Technology Centers at the California NanoSystems Institute.
News Article | April 14, 2016
UCLA and Caltech researchers have developed a technique that shows promise for preventing drug resistance in people with glioblastoma, the most common and deadliest type of brain cancer. Drug resistance is one of the primary obstacles in treating glioblastoma — it is extremely common and affects virtually all people with the disease. But there is no consensus on why the body stops responding to treatment after a period of time, and scientists don’t yet have a tool for predicting drug resistance during the early stages of treatment. The new technique uses penny-sized microfluidic chips that are equipped with minuscule DNA “bar codes,” which are no bigger than a single cell. Glioblastoma tumors can grow rapidly and spread throughout the brain. The aggressive behavior is triggered by genetic mutations that cause the tumor cells’ protein signaling networks to become overly active. As a result, glioblastoma cells continuously receive signals that make them grow, divide and invade healthy tissue in the brain. The current treatments for glioblastoma are designed to disrupt specific elements of the protein networks and to block the signaling that powers the tumor cells. But even when that approach is successful, it usually only works for a short time before the body becomes resistant to the treatment. A paper about the new approach was published in the journal Cancer Cell. The research was led by James Heath, co-director of the UCLA Jonsson Comprehensive Cancer Center’s Nanotechnology Program. Heath and his team looked at how glioblastoma responded to a drug called CC214-2, which targets a signaling protein called mTOR. Mice with glioblastoma initially responded to CC214-2, but after a month they started to resist the drug, and their tumors began to grow again. The researchers collected information from the microfluidic chips, which allowed them to anticipate resistance from a single or combination cancer treatment. They also found that within only two days after administering CC214-2, the cancer cells were adapting to the drug, and their ability to adapt foreshadowed full-scale drug resistance. The cancer cells’ response to the drug was analogous to how automobile traffic responds to a road closure — they simply found new molecular routes through which to maintain their hyperactive signaling. In other words, the very cancer cells that had responded to the drug initially were the same ones that became resistant to the drug over time. The single-cell analysis also showed the researchers the specific “traffic patterns” the cells used to get around the inhibiting influence of the drug, which gave the scientists key insights about the drug combinations they could use to inhibit the mTOR protein and the proteins that provided the alternate signaling routes. Previous findings had suggested that drug resistance against targeted inhibitors for glioblastoma or other tumors likely occurred from one generation of cancer cells to the next — meaning that the cells could randomly develop genetic mutations that either disrupt the drug binding or counteract its effects — rather than because of individual cells’ ability to adapt. The new study was one of the first to show that cancer cells can adapt to drug treatments without genetic changes by rewiring their internal signaling circuitry. “By sensing this adaptation so early, we were able to anticipate and treat drug resistance,” says Heath, who is also the Elizabeth W. Gilloon Professor of Chemistry at Caltech. The scientists used their single cell measurements to predict three drug combinations that would stop tumor growth over the long term, as well as four drugs or drug combos that would likely have no effect. While testing all seven predictions, they found that each prediction was correct. The findings have also shown positive results in mammal models with melanoma. The research team also included Dr. Tim Cloughesy, a member of the Jonsson Cancer Center and professor and director of the UCLA department of neurology; Wei Wei, a first author of the study and an assistant professor of molecular and medical pharmacology at the David Geffen School of Medicine at UCLA; and Dr. Paul Mischel, a former UCLA faculty member who is now a professor at UC San Diego’s Ludwig Institute for Cancer Research. The research was supported by the Ben and Catherine Ivy Foundation, the National Cancer Institute and the Jean Perkins Foundation. Heath is the founder and a board member of Isoplexis, a company that is seeking to commercialize the technologies used in the study.
News Article | February 15, 2017
Scalp cooling can lessen some chemotherapy-induced hair loss - one of the most devastating hallmarks of cancer - in certain breast cancer patients, according to a new multicenter study from UC San Francisco, Weill Cornell Medicine and three other medical centers. A majority of the study's patients, all women with stage 1 or 2 breast cancer who underwent scalp cooling, retained more than half of their hair after completing chemotherapy, the investigators learned. The study, which tracks patients over five years, used standardized photographs to grade hair loss. The study will be published Feb. 14 in JAMA, the Journal of the American Medical Association. "Hair loss is almost universal among breast cancer patients receiving adjuvant chemotherapy and is one of the most distressing of adverse side effects," said first author Hope S. Rugo, MD, the corresponding author who led the study. Rugo is a UCSF professor of medicine specializing in breast cancer research and treatment, and director of the breast oncology and clinical trials education program at the UCSF Helen Diller Family Comprehensive Cancer Center. "We found that scalp cooling during commonly used chemotherapy regimens was well tolerated and was associated with significantly less hair loss, as well as improvement in several quality-of-life indicators," Rugo said. "While further research is needed, the data suggest that when scalp cooling is successful at decreasing hair loss, it could improve the treatment experience for women undergoing adjuvant chemotherapy for early-stage breast cancer." Breast cancer is the most common cancer in women around the world, both in developed countries and less developed ones, according to the World Health Organization. Scalp cooling has been used in more than 30 countries as a way to potentially prevent hair loss in patients receiving chemotherapy; in Europe it's been used for several decades. Two types of cooling caps are typically used: frozen caps that need to be replaced every half hour, or cooling systems that continually circulate coolants into a cap during the entire chemotherapy session. Scalp cooling is thought to reduce hair loss due to reduced delivery of chemotherapy to the scalp and hair follicle, Rugo said. The cold temperatures also are thought to slow the hair follicle cell division, making the cell less susceptible to the damaging effects of chemotherapy. In the United States, scalp cooling has been limited because of factors including insufficient scientific data and concern about the theoretic risk of scalp metastases. For the JAMA study, researchers investigated the effectiveness of one device: the DigniCap scalp cooling system manufactured by the Swedish public company Dignitana AB, which partly funded the research. In December 2015, based on preliminary results from the study, the U.S. Food and Drug Administration cleared the DigniCap for use in the U.S., the first and only cooling cap to date to receive such clearance. In the JAMA paper, 122 women with stage 1or stage 2 breast cancer were studied - all received non-anthracycline adjuvant chemotherapy, which generally causes severe hair loss. Of those women, 101 were enrolled in scalp cooling; 16 others, also undergoing chemotherapy but not scalp cooling, were in the control arm. Scalp cooling began 30 minutes prior to each chemotherapy cycle and involved a close fitting of the silicone cap on the patient's head, followed by an insulating neoprene cap. The silicone cap was then gradually cooled. The DigniCap is set to cool at 3 degrees Celsius (37 degrees Fahrenheit) with a temperature variance of plus or minus 2 degrees. Of 101 patients who underwent scalp cooling, 67 of them (66.3 percent) retained half or more of their hair, the authors wrote. In the parallel control group, all the patients lost their hair. Additionally, three of five quality-of-life measures were significantly better for the women who underwent scalp-cooling, including feeling more physically attractive. "Enabling a woman to preserve her hair during chemotherapy is empowering," said senior author Tessa Cigler, MD, MPH, an assistant professor of clinical medicine in the Weill Cornell Breast Center at Weill Cornell Medicine. "Scalp cooling allows patients to protect their privacy and maintain their self-esteem and sense of well-being. This study provides long-awaited evidence for an effective and practical scalp cooling method." The mean age of the cold cap patients was 53 years. Some 77 percent of the patients were white, 9 percent were black and nearly 11 percent were Asian. The study was conducted between August 2013 and October 2014. The average duration of chemotherapy was 2.3 months. Many of the patients reported mild headaches or scalp pain associated with the scalp cooling. Two patients discontinued scalp cooling due to feeling cold. There has been no evidence of scalp metastases in any patient after approximately 30 months of follow up. All patient follow up will continue for a total of five years. The study was funded partially by the Lazlo Tauber Family Foundation (awarded to UCSF); the Anne Moore Breast Cancer Research Fund (awarded to Weill Cornell Medicine); and the Friedman Family Foundation (awarded to Mount Sinai Beth Israel). Dignitana AB supported the design and conduct of the study, including collection, management, analysis and interpretation of the data. Study co-authors also included researchers from the Icahn School of Medicine at Mount Sinai, New York; Wake Forest Baptist Health Medical Center; and the Jonsson Comprehensive Cancer Center at UCLA. From UCSF, co-authors are Michelle E. Melisko, MD, and Laura Esserman, MD, MBA; from Weill Cornell Medicine, Anne Moore, MD, was also a co-author. A complete list of authors can be found in the paper. About UCSF: UC San Francisco (UCSF) is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care. It includes top-ranked graduate schools of dentistry, medicine, nursing and pharmacy; a graduate division with nationally renowned programs in basic, biomedical, translational and population sciences; and a preeminent biomedical research enterprise. It also includes UCSF Health, which comprises three top-ranked hospitals, UCSF Medical Center and UCSF Benioff Children's Hospitals in San Francisco and Oakland, and other partner and affiliated hospitals and healthcare providers throughout the Bay Area. Please visit http://www. . About Weill Cornell Medicine: Weill Cornell Medicine is committed to excellence in patient care, scientific discovery and the education of future physicians in New York City and around the world. The doctors and scientists of Weill Cornell Medicine - faculty from Weill Cornell Medical College, Weill Cornell Graduate School of Medical Sciences, and Weill Cornell Physician Organization - are engaged in world-class clinical care and cutting-edge research that connect patients to the latest treatment innovations and prevention strategies. Located in the heart of the Upper East Side's scientific corridor, Weill Cornell Medicine's powerful network of collaborators extends to its parent university Cornell University; to Qatar, where an international campus offers a U.S. medical degree; and to programs in Tanzania, Haiti, Brazil, Austria and Turkey. Weill Cornell Medicine faculty provide comprehensive patient care at New York-Presbyterian/Weill Cornell Medical Center, New York-Presbyterian/Lower Manhattan Hospital and New York-Presbyterian/Queens. Weill Cornell Medicine is also affiliated with Houston Methodist. For more information, visit Weill.Cornell.edu.
News Article | January 7, 2016
UCLA scientists have developed a promising novel method to treat gynecologic tumors. The approach focuses on a protein called p53, which is commonly mutated in women who have high-grade serous ovarian cancer, the deadliest form of reproductive cancer. In many women with the disease, the cancer is very advanced by the time it is diagnosed and is therefore difficult to treat. The discovery was the result of a three-year study co-led by David Eisenberg and Dr. Sanaz Memarzadeh, members of the UCLA Jonsson Comprehensive Cancer Center. The findings, which were published online in the journal Cancer Cell, could ultimately lead to new targeted therapies for many other types of cancer carrying similar p53 mutations. P53 is known as the “guardian of the genome.” It prevents damaged cells from reproducing by stopping their growth until the damage is repaired or, if the damage cannot be reversed, promotes cell death. But mutations, which are found in 96 percent of patients with high-grade serous ovarian tumors, can cause p53 to form clumps, or “aggregates,” which impair the protein’s normal function. As a result, the damaged cells are able to multiply uncontrollably, which can lead to cancer. The UCLA scientists developed and tested a peptide called ReACp53, which penetrates cancer cells and prevents mutated p53 from clumping together. The technique restores normal p53 function, causing death of the ovarian cancer cells. “Our lab has worked for 15 years on the protein aggregates that cause amyloid diseases such as Alzheimer’s and Parkinson’s disease,” said Eisenberg, who also is a professor of biological chemistry and a member of UCLA–DOE Institute. “These aggregates are organized as fibers that are 500 times smaller than the width of a hair, which is quite a challenge.” “This approach was originally developed for neurodegenerative diseases and we are now applying it to cancer therapy,” said Alice Soragni, a UCLA postdoctoral scholar in Eisenberg’s lab and first author of the study. “We identified the sticky segments of p53 that cause the protein to clump by using a computer algorithm, determined their structure and then designed ReACp53 to block this process,” Soragni added. “This can keep the protein from clumping so it can do its job and kill cancer cells.” The researchers isolated tumor cells from patients and grew them to reproduce small tumors in the lab dish. The “mini-tumors” are extremely useful for drug development because they faithfully replicate several features of the original cancer. “The results were remarkable, with significant shrinkage in patient-derived tumors,” said Memarzadeh, who also is a UCLA associate professor of obstetrics and gynecology the director of the G.O. Discovery Laboratory at the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research. She added that the approach produced no obvious side effects in a physiological model and that ReACp53 was very well tolerated. More than 80 percent of women with advanced stage high-grade serous ovarian cancer experience relapses even after repeated surgeries and multiple rounds of chemotherapy, and this effective new approach to treat the disease could be a major step forward in preventing cancer from returning. More than 15,000 women a year in the U.S. die from all types of ovarian cancer. The study was funded by the UCLA Jonsson Cancer Center Foundation, the Elsa U. Pardee Foundation, the Howard Hughes Medical Institute and the National Institutes of Health. UCLA has licensed ReACp53 and the technology used to develop it to ADRx, Inc., a biopharmaceutical company co-founded by Eisenberg.
News Article | February 15, 2017
Sandra Horning, MD, Chief Medical Officer and executive vice president of global development for Roche and Genentech, a member of the Roche Group, has been named the 2017 recipient of the Duane Roth Memorial Award, which will be presented February 16 at the annual Industry/Academia Translational Oncology Symposium at UC San Diego Moores Cancer Center. The award celebrates Duane Roth, who was Chief Executive Officer of Connect, a San Diego-based organization that promotes technology innovation and entrepreneurship. Roth died in 2013 from injuries suffered in a bicycling accident. Horning has had a long and distinguished career in cancer treatment and research, first as a practicing oncologist, investigator and professor at Stanford University for 25 years, then at the San Francisco-based biotech company Genentech, which merged with the Swiss firm Roche in 2009. Horning, a cancer survivor, has focused much of her work on developing new treatments for lymphoma, a cancer that affects the immune system, including leading clinical trials that eventually resulted in new, approved drug treatments. She was president of the American Society of Clinical Oncology in 2005-2006. "Throughout her impressive career, Sandra Horning has been an unwavering champion of personalized therapies and shifting the focus from treatment of cancer to a more holistic approach of treating the patient as an individual, mindful of his or her family and anticipating survivorship issues, such as fertility, secondary malignancies, cardiopulmonary and endocrine side-effects and more," said Ida Deichaite, PhD, director of UC San Diego Moores Cancer Center's Office of Industry Relations and an organizer of the symposium. "Her scientific achievements in oncology have been amazing and continue to give life, but it's her passion and commitment to promoting empathetic treatment plans that exemplify how establishing collaborations across disciplines can truly improve cancer treatment." The Roth award is bestowed upon leaders in health care whose work has overcome numerous scientific, financial, institutional, political and cultural obstacles to create new paradigms in research and treatment, said Deichaite. Past recipients include: Dennis Slamon, MD, PhD, UCLA Jonsson Comprehensive Cancer Center; Brian Druker, MD, Knight Institute at Oregon Health and Science University; and Laura Esserman, MD, UCSF Helen Diller Family Comprehensive Cancer Center. The symposium, now in its 13th year, is a day-long event at Moores Cancer Center, bringing together scientists, physicians and biopharma representatives to discuss innovations and new collaborations in cancer research and treatment.
News Article | December 5, 2016
Researchers from the UCLA Department of Medicine, Division of Hematology Oncology and the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA have published two studies that define how key genetic factors affect blood-forming stem cells by either accelerating or hindering the cells' regenerative properties. The findings could one day lead to improved treatments for people undergoing common therapies for cancer such as chemotherapy and radiation. Blood-forming stem cells, or hematopoietic stem cells, are found in the bone marrow. These cells have two unique properties: They can self-renew and, through a process called differentiation, they can form any type of blood cell. A healthy immune system depends on the regenerative abilities of hematopoietic stem cells. Common cancer therapies such as chemotherapy and radiation can eliminate cancer by killing cancer cells. But these treatments also damage hematopoietic stem cells, which can impede the cells' ability to regenerate blood, slowing the immune system and resulting in a longer, more complicated recovery for people with cancer. Previous research indicated that certain genes may alter hematopoietic stem cells' regenerative capacity by either accelerating or hindering the cells' ability to restore the immune system, but more research was needed to pinpoint the specific genetic activity and effects. One of the new studies focused on a gene called Grb10 that is expressed by hematopoietic stem cells. Grb10's function was previously not known, so to better understand its role, the scientists deleted Grb10 from hematopoietic stem cells in lab dishes and in mice that had received radiation. They found that deleting Grb10 strongly promotes hematopoietic stem cell self-renewal and differentiation. In the other study, researchers analyzed a protein called DKK1. DKK1 is produced by a gene expressed by a specific "bone progenitor" cell that is present in the "niche," or cellular environment, that surrounds the hematopoietic stem cell. Typically, bone progenitor cells regenerate bone, but scientists had previously hypothesized that these cells also play an important role in regulating hematopoietic stem cells' ability to self-renew and differentiate into other blood cells. "The cellular niche is like the soil that surrounds the stem cell 'seed' and helps it grow and proliferate," said Dr. John Chute, professor of medicine in the Division of Hematology Oncology in the UCLA David Geffen School of Medicine and the study's senior author. "Our hypothesis was that the bone progenitor cell in the niche may promote hematopoietic stem cell regeneration after injury." The researchers showed that adding DKK1 to hematopoietic stem cells in lab dishes and mice that had received radiation produced a cascade effect within the cell niche that greatly enhanced hematopoietic stem cells' ability to self-renew and differentiate into other blood cells. Taken together, the studies uncover two molecular mechanisms that could potentially be manipulated to increase the regenerative properties of hematopoietic stem cells and improve cancer therapy. Scientists can now test drugs that inhibit Grb10 or test the effectiveness of administering DKK1 intravenously to promote immune regeneration in people who have received chemotherapy and radiation or those undergoing bone marrow transplants. Chute, who also is a member of the UCLA Jonsson Comprehensive Cancer Center, is the senior author of both papers. The first author of the Nature Medicine study is Heather Himburg and other authors are Mamle Quarmyne, Xiao Yan, Joshua Sasine, Liman Zhao, Grace Hancock, Jenny Kan, Katie Pohl and Evelyn Tran of UCLA; and Phuong Doan, Nelson Chao and Jeffrey Harris of Duke University. Other authors of the Cell Reports study are Yan, Himburg, Pohl, Quarmyne, Tran, Yurun Zhang, Tianchang Fang, Kan and Zhao of UCLA; and Doan and Chao of Duke University. The studies were published in the journals Nature Medicine (embargo lifts at 11:00 a.m. US Eastern time on Monday, December 5, 2016) and Cell Reports (published on November 1, 2016). The studies were funded by grants from the National Heart, Lung, and Blood Institute (HL-086998-05), the National Institute of Allergy and Infectious Diseases (AI-067798), a California Institute for Regenerative Medicine Leadership Award (LA1-08014), a National Institute of Allergy and Infectious Diseases' Centers for Medical Countermeasures Against Radiation Pilot Award (2U19AI067773-11), and by the UCLA Broad Stem Cell Research Center.
O'Connell R.M.,University of Utah |
Rao D.S.,Laboratory Medicine |
Rao D.S.,Jonsson Comprehensive Cancer Center |
Rao D.S.,University of California at Los Angeles |
And 2 more authors.
Annual Review of Immunology | Year: 2012
The mammalian inflammatory response is a rapid and complex physiological reaction to noxious stimuli including microbial pathogens. Although inflammation plays a valuable role in combating infection, its dysregulation often occurs in people and can cause a variety of pathologies, ranging from chronic inflammation, to autoimmunity, to cancer. In recent years, our understanding of both the cellular and molecular networks that regulate inflammation has improved dramatically. Although much of the focus has been on the study of protein regulators of inflammation, recent evidence also points to a critical role for a specific class of noncoding RNAs, called microRNAs (miRNAs), in managing certain features of the inflammatory process. In this review, we discuss recent advances in our understanding of miRNAs and their connection to inflammatory responses. Additionally, we consider the link between perturbations in miRNA levels and the onset of human inflammatory diseases. © 2012 by Annual Reviews. All rights reserved.
Cole S.W.,University of California at Los Angeles |
Cole S.W.,Jonsson Comprehensive Cancer Center |
Cole S.W.,Norman Cousins Center |
Sood A.K.,University of Houston
Clinical Cancer Research | Year: 2012
Beta-adrenergic signaling has been found to regulate multiple cellular processes that contribute to the initiation and progression of cancer, including inflammation, angiogenesis, apoptosis/anoikis, cell motility and trafficking, activation of tumor-associated viruses, DNA damage repair, cellular immune response, and epithelial-mesenchymal transition. In several experimental cancer models, activation of the sympathetic nervous system promotes the metastasis of solid epithelial tumors and the dissemination of hematopoietic malignancies via β-adrenoreceptor-mediated activation of protein kinase A and exchange protein activated by adenylyl cyclase signaling pathways. Within the tumor microenvironment, β-adrenergic receptors on tumor and stromal cells are activated by catecholamines from local sympathetic nerve fibers (norepinephrine) and circulating blood (epinephrine). Tumor-associated macrophages are emerging as key targets of β-adrenergic regulation in several cancer contexts. Sympathetic nervous system regulation of cancer cell biology and the tumor microenvironment has clarified the molecular basis for long-suspected relationships between stress and cancer progression, and now suggests a highly leveraged target for therapeutic intervention. Epidemiologic studies have linked the use of β-blockers to reduced rates of progression for several solid tumors, and preclinical pharmacologic and biomarker studies are now laying the groundwork for translation of β-blockade as a novel adjuvant to existing therapeutic strategies in clinical oncology. ©2011 AACR.