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THE 3RD STAT4ONC ANNUAL SYMPOSIUM APRIL 25-27, 2019, HILTON, HARTFORD, CONNECTICUT, 315 Trumbull St, Hartford, CT 06103

Reporter: Stephen J. Williams, Ph.D.

SYMPOSIUM OBJECTIVES

The three-day symposium aims to bring oncologists and statisticians together to share new research, discuss novel ideas, ask questions and provide solutions for cancer clinical trials. In the era of big data, precision medicine, and genomics and immune-based oncology, it is crucial to provide a platform for interdisciplinary dialogues among clinical and quantitative scientists. The Stat4Onc Annual Symposium serves as a venue for oncologists and statisticians to communicate their views on trial design and conduct, drug development, and translations to patient care. To be discussed includes big data and genomics for oncology clinical trials, novel dose-finding designs, drug combinations, immune oncology clinical trials, and umbrella/basket oncology trials. An important aspect of Stat4Onc is the participation of researchers across academia, industry, and regulatory agency.

Meeting Agenda will be announced coming soon. For Updated Agenda and Program Speakers please CLICK HERE

The registration of the symposium is via NESS Society PayPal. Click here to register.

Other  2019 Conference Announcement Posts on this Open Access Journal Include:

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Cell Therapy Market to Grow Beyond Oncology As Big Pharma Expands Investments

Reporter: Irina Robu, PhD

Collaborations of Big Pharma with small to mid-segment companies are currently focusing R&D on precision medicine. The market is valued at $2.70 billion in 2017 and is expected to reach $8.21 billion in 2025. A varied therapeutic focus and implementation of advanced manufacturing technologies such as single-use bioreactors, will pave a way for unique cell-gene and stem cell – gene combination therapies.
Novartis and Gilead are the first companies to adopt pay for performance business for their CAR-T cell therapies. In addition to innovative pricing models, Pharma companies are also showing a preference for risk sharing and fast-to-market models in order to support the development of novel therapies. Moreover, developments in cell culturing techniques alongside the use of different stem cells such as adipose-derived stem cells, mesenchymal stem cells, and induced pluripotent stem cell will reinforce the market with superior treatment options for non-oncological conditions such as neurological, musculoskeletal, and dermatological conditions.

With the high request for cell therapies, numerous growth opportunities can occur such as:

  • With more than 959 ongoing regenerative medicine clinical trials, the market finds opportunity across both stem cell and non-stem cell-based therapies.
  • Curative combination therapies which help find application in identifying the right patient as well as predicting the immune response in cancer patients.
  • Implementation of IT solutions and single-use manufacturing techniques for optimizing small-volume, high-value manufacturing of novel cell therapies, thus dropping the time to market radically.
  • Emerging Business Models which aid market players focus on academic and research collaborations together with industry collaborations to support therapeutic and technological innovations.

Source

https://www.newswire.ca/news-releases/cell-therapy-market-to-grow-beyond-oncology-as-big-pharma-expands-investments-826628110.html

 

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City of Hope, Duarte, California – Combining Science with Soul to Create Miracles at a Comprehensive Cancer Center designated by the National Cancer InstituteAn Interview with the Provost and Chief Scientific Officer of City of Hope, Steven T. Rosen, M.D.

Author: Gail S. Thornton, M.A.

Co-Editor: The VOICES of Patients, Hospital CEOs, HealthCare Providers, Caregivers and Families: Personal Experience with Critical Care and Invasive Medical Procedures

 

City of Hope (https://www.cityofhope.org/homepage), a world leader in the research and treatment of cancer, diabetes, and other serious diseases, is an independent, biomedical research institution and comprehensive cancer center committed to researching, treating and preventing cancer, with an equal commitment to curing and preventing diabetes and other life-threatening diseases. Founded in 1913, City of Hope is one of only 47 comprehensive cancer centers in the nation, as designated by the National Cancer Institute.

City of Hope possesses flexibility that larger institutions typically lack. Innovative concepts move quickly from the laboratory to patient trials — and then to market, where they benefit patients around the world.

As a founding member of the National Comprehensive Cancer Network, their research and treatment protocols advance care throughout the nation. They are also part of ORIEN (Oncology Research Information Exchange Network), the world’s largest cancer research collaboration devoted to precision medicine. And they continue to receive the highest level of accreditation by the American College of Surgeons Commission on Cancer for their exceptional level of cancer care.

As an innovator, City of Hope is a pioneer in bone marrow and stem cell transplants with one of the largest and most successful of its kind in the world. Other examples of its leadership and innovation include,

  • Numerous breakthrough cancer drugs, including Herceptin, Rituxan, Erbitux, and Avastin, are based on technology pioneered by City of Hope and are saving lives worldwide.
  • To date, City of Hope surgeons have performed more than 10,000 robotic procedures for prostate, kidney, colon, liver, bladder, gynecologic, oral and other cancers.
  • They are a national leader in islet cell transplantation, which has the potential to reverse type 1 diabetes, and also provide islet cells for research at other institutions throughout the U.S.
  • Millions of people with diabetes benefit from synthetic human insulin, developed through research conducted at City of Hope.
  • Their scientists are pioneering the application of blood stem cell transplants to treat patients with HIV- and AIDS related lymphoma. Using a new form of gene therapy, their researchers achieved the first long-term persistence of anti-HIV genes in patients with AIDS-related lymphoma — a treatment that may ultimately cure lymphoma and HIV/AIDS.

 

Additionally, City of Hope has three on-campus manufacturing facilities producing biologic and chemical compounds to good manufacturing practice (GMP) standards.

City of Hope launched its Alpha Clinic, thanks to an $8 million, five-year grant from the California Institute for Regenerative Medicine (CIRM). The award is part of CIRM’s Alpha Stem Cell Clinics program, which aims to create one-stop centers for clinical trials focused on stem cell treatments for currently incurable diseases. The Alpha Clinics Network is already running 35 different clinical trials involving hundreds of patients, 17 of which are being conducted at City of Hope. Current clinical trials include transplants of blood stem cells modified to treat patients with AIDS and lymphoma, neural stem cells to deliver drugs directly to cancers hiding in the brain, and T cell immunotherapy trials.

Located just northeast of Los Angeles, landscaped gardens and open spaces surround City of Hope’s leading-edge medical and research facilities at its main campus in Duarte, California. City of Hope also has 14 community practice clinics throughout Southern California.

COH robotic (1)COH Helford H (1)COH1 Dr__Rosen_Clinic-2 (2)COH8 Janice_Huss-7COH7 COH_1369COH6 GMP_0454COH4 DSC_9279

Image SOURCE: Photographs courtesy of City of Hope, Duarte, California. Interior and exterior photos of the City of Hope, including Dr. Steven T. Rosen and his team.

 

Below is my interview with the Provost and Chief Scientific Officer of City of Hope, Steven T. Rosen, M.D., which occurred in April, 2017.

 

What sets City of Hope apart from other hospitals and research centers?

Dr. Rosen: City of Hope offers a unique blend of compassionate care and research innovation that simply can’t be found anywhere else.

We’re more than a medical center, and more than a research facility. We take the most compassionate patient-focused care available, combine it with today’s leading-edge medical advances, and infuse both with a quest to deliver better outcomes.

I’m proud to say that we’re known for rapidly translating scientific research into new treatments and cures, and that our technology has led to the development of four of the most widely used cancer-fighting drugs, Herceptin (trastuzumab), Avastin (bevacizumab), Erbitux (cetuximab), and Rituxin (rituximab).

City of Hope is a family. Our special team of experts treats the whole person and the family, not just a body, or a case or a disease. In fact, some of our patients have shared their stories of success. It is gratifying for me and our many health professionals to be able to make a positive difference in their lives.

Eleven years ago, Los Angeles firefighter Gus Perez was facing a battle far greater than any he’d ever known. He was diagnosed with CML (chronic myelogenous leukemia). Gus began receiving the drug Gleevec, which put him into remission. Given the drug’s success, he almost resigned himself to staying on it, yet was drawn to another option: undergoing a bone marrow transplant at City of Hope. “I went to my favorite ocean spot,” Gus recalls. “I put on my wetsuit, like I’ve done thousands of times, and paddled out. Every wave was special because I wasn’t sure if I was ever going to be back. And I remember getting out of the water and counting the steps to my car, thinking, ‘I’m going to beat this. I’m going to retrace those steps.’ And I’m happy to say I was able to do it.” Gus and his family recently celebrated the 10th anniversary of his bone marrow transplant. “City of Hope is more than just medical treatment,” Gus says. “They have to put you back together from the ground up. And to me, that’s truly a miracle.”

 

As an active 14-year-old, Nicole Schulz loved cheerleading and hanging out with her friends. Then her whole world changed. Nicole learned that her fatigue and other symptoms weren’t “just the flu,” but the effects of acute myelogenous leukemia (AML), an aggressive disease that rendered her bone marrow 97 percent cancerous. Nicole spent the next three and a half months at City of Hope, fighting the cancer with a daily regimen of chemotherapy and blood and platelet transfusions. “It put me into remission,” Nicole says. “But I wasn’t cured. And I wanted a cure.” Fortunately, Nicole was a candidate for a bone marrow transplant. Her malfunctioning marrow cells would be replaced with healthy marrow from a matching unrelated donor. “I never gave up — and neither did City of Hope,” Nicole says. After two bone marrow transplants and tremendous perseverance, Nicole is back to living the life she once knew and quickly making up for lost time.

 

When Jim Murphy’s doctor called and asked to see him on Christmas Eve, Jim knew it wasn’t going to be good news. And he was right. “The diagnosis was esophageal cancer,” Jim says. “Once they tell you that, there’s nothing you can do but formulate your action plan.” Jim would need to undergo chemotherapy, radiation and surgery to remove the tumor from his esophagus. It would require taking two-thirds of his esophagus and a third of his stomach. Despite the intense treatment, Jim was determined to keep his life as normal as possible. Throughout his chemotherapy and radiation therapy, he never missed a day of work, even riding his mountain bike to and from City of Hope to take his treatments. “I needed to show myself one victory after another,” Jim says. “I know City of Hope appreciated the fact that I was fighting as hard as they were.” Now cancer-free for several years, Jim credits City of Hope with giving him the best chance to fight his disease. “What really impressed me was that the research was right there at City of Hope. If they have something experimental, it goes from the researcher, right to the doctor and right to you. It’s the ultimate weapon — doctors reaching out for researchers, researchers reaching out for doctors. And the patient wins.”

 

City of Hope is a pioneer in the fields of bone marrow transplantation, diabetes and breakthrough cancer drugs based on technology developed at the institution.  How are you transforming the future of health care by turning science into a practical benefit for patients? 

Dr. Rosen: This is a distinctive place where brilliant research moves rapidly from concept to cure. That’s what we do—we speed breakthroughs in the lab to benefit patients in the clinic

Many know us for our leadership in fighting cancer, but fighting cancer is only part of our story. For decades, we’ve been making history in the fight against diabetes and other life-threatening illnesses that can be just as dangerous, and shattering, to patients and their families.

Every year, we conduct 400+ clinical trials, enrolling 6,000+ patients; hold 300+ patents and submit nearly 30 applications to the U.S. Food and Drug Administration (FDA) for investigational new drugs; and offer comprehensive assistance for patients and their families, including patient education, support groups, social resources, mind-body therapies and patient navigators.

We also translate breakthrough laboratory findings into real, lifesaving treatments and cures, and manufacture them at three on-campus facilities. Our goal is to get patients the treatments they need as fast as humanly possible.

We are in the race to save lives – and win. In our research efforts, we are teaching immune cells to attack tumors and Don J. Diamond [Ph.D.], Vincent Chung, [M.D.], and other City of Hope researchers launched a clinical trial seeking ways to effectively activate a patient’s own immune system to fight his or her cancer. The team is combining an immune-boosting vaccine with a drug that inhibits tumor cells’ ability to grow — to encourage immune cells to attack and eliminate tumors such as non-small cell lung cancer, melanoma, triple-negative breast cancer, renal cell carcinoma and many other cancer types.

City of Hope’s Diabetes & Metabolism Research Institute is committed to developing a cure for type 1 diabetes (T1D) within six years, fueled by a $50 million funding program led by the Wanek family. Research is already underway to unlock the immune system’s role in diabetes, including T cell modulation and stem cell-based therapies that may reverse the autoimmune attack on islet cells in the pancreas, which is the cause of T1D. City of Hope’s Bart Roep [Ph.D.], previously worked at Leiden University Medical Center in the Netherlands, where he was instrumental in launching a phase 1 clinical trial for a vaccine that aims to spur the immune system to fight, and possibly cure, T1D. Plans are developing for a larger, phase 2 trial to launch in the future at City of Hope.

 

What makes your recent alliance with Translational Genomics Research Institute (TGen) different from other efforts in precision medicine around the country and within our Government to identify treatments for cancer?

Dr. Rosen: Precision medicine is the future of cancer care. Since former Vice President’s Joe Biden’s Moonshot Cancer program was launched to achieve 10 years of progress in preventing, diagnosing and treating cancer, within five years, federal cancer funding has been prioritized to address these aims.

City of Hope and the Translational Genomics Research Institute (TGen) have formed an alliance to fast-track the future of precision medicine for patients. Our clinical leadership as a comprehensive cancer center combined with TGen’s leadership in molecular cancer research will propel us to the forefront of precision medicine and is further evidence of our momentum in transforming the future of health.

In fact, most recently scientists at TGen have identified a potent compound in the fight for an improved treatment against glioblastoma multiforme (GBM), the most common and deadly type of adult brain cancer. This research could represent a breakthrough for us to find an effective long-term treatment. The compound prevents glioblastoma from spreading, and leaves cancer vulnerable to chemotherapy and radiation.  Aurintricarboxylic Acid (ATA) is a chemical compound that in laboratory tests was shown to block the chemical cascade that otherwise allows glioblastoma cells to invade normal brain tissue and resist both chemo and radiation therapy.

The goal is to accelerate the speed at which we advance research discoveries into the clinic to benefit patients worldwide.

 

As a prestigious Comprehensive Cancer Center, City of Hope was named this year as one of the top 20 cancer centers for the past 10 years. How do you achieve that designation year after year? And what specific collaborations, clinical trials and multidisciplinary research programs are under way that offer benefits to patients?

Dr. Rosen: It’s simple – we achieve this through the compassion, commitment and excellence of the City of Hope family, which includes our world-class physicians, staff, supporters and donors.

We look to find the best and brightest professionals and bring them to City of Hope to work with our amazing staff on research, treatments and cures that not only change people’s lives, but also change the world.

We also have a community of forward-looking, incredibly generous and deeply committed supporters and donors. People who get it. People who share our vision. People who take their capacity for business success and apply it to helping others. They provide the fuel that drives us forward, enabling us to do great things.

City of Hope has a long track record of research breakthroughs and is constantly working to turn novel scientific research into the most advanced medical services.

Right now, we have a number of collaborative programs underway, including: Our alliance with TGen to make precision medicine a reality for patients, The Wanek Family Project to Cure Type 1 Diabetes, and Immunotherapy and CAR-T cell therapy clinical trials, which aim to fight against brain tumors and blood cancers.

More specifically, our research team led by Hua Yu, [Ph.D.] and Andreas Herrmann, [Ph.D.], developed a drug to address the way in which cancer uses the STAT3 protein to “corrupt” the immune system. The drug, CpG-STAT3 siRNA, halts the protein’s ability to “talk” to the immune system. It blocks cancer cell growth while sending a message to surrounding immune cells to destroy a tumor, and it may also enhance the effectiveness of other immunotherapies, such as T-cell therapy.

We could also see a functional cure for HIV in the next 5 to 10 years. Gene therapy pioneer, John A. Zaia, [M.D.], the Aaron D. Miller and Edith Miller Chair in Gene Therapy, the director of the Center for Gene Therapy within City of Hope’s Hematologic Malignancies and Stem Cell Transplantation Institute, as well as principal director of our Alpha Clinic, and researchers are building on knowledge gained from the case of the so-called “Berlin patient” whose HIV infection vanished after receiving a stem cell transplant for treatment of leukemia. The donor’s CCR5 gene, HIV’s typical pathway into the body, had a mutation that blocked the virus. The team launched a clinical trial that used a zinc finger nuclease to “cut out” the CCR5 gene, leaving HIV with no place to go. Their goal: to someday deliver a one-time treatment that produces a lifetime change. Integral to the first-in-human trials are the nurses who understand the study protocols, potential side effects and symptoms.

 

Would you share some of the current science under way on breakthrough cures for cancer?

Dr. Rosen: We are achieving promising results in many innovative approaches – gene therapy, targeted therapy, immunotherapy and all aspects of precision medicine. We are also forging new partnerships and collaboration agreements around the world.

Let me share with you a few examples of our cutting-edge science.

City of Hope researchers identified a promising new strategy for dealing with PDAC, an aggressive form of pancreatic cancer. The bacterial-based therapy homes to tumors and provokes an extremely effective tumor-killing response.

Teams at City of Hope are working to load nanoparticles with small snippets of DNA molecules that can stimulate the immune system to attack tumor cells in the brain. This innovative approach can overcome the blood-brain barrier, which blocks many drugs from reaching the tumor site.

A pioneer in islet cell transplantation for the treatment of diabetes, City of Hope conducted a clinical trial to refine its transplantation protocol. Because this new protocol includes an ATG (antithymoglobulin) induction, the immune system will not harm the transplant. The immune-suppression strategy used in the trial is considered a significant improvement over the protocol used in previous islet cell transplant trials.

City of Hope physicians and scientists joined a multinational team in reporting the success of a phase II clinical trial of a novel drug against essential thrombocythemia (ET). ET patients make too many platelets (cells essential for blood clotting), which puts them at risk for abnormal clotting and bleeding. All 18 patients treated with the drug, imetelstat, exhibited decreased platelet levels, and 16 showed normalized blood cell counts.

Researchers found that the CMVPepVax vaccine — developed at City of Hope to boost cellular immunity against cytomegalovirus (CMV) — is safe and effective in stem cell transplant recipients. Building on this discovery, City of Hope and Fortress Biotech formed a company to develop two vaccines, PepVax and Triplex, against CMV, a life-threatening illness in people who have weakened or underdeveloped immune systems such as cancer patients and developing fetuses. The vaccines are the subjects of multisite clinical trials. These City of Hope vaccines could open the door to a new way of protecting cancer patients from CMV, a devastating infection that affects hundreds of thousands of people worldwide.

 

In what ways does the initial vision of Samuel H. Golter impact the work you are doing today? What does the tagline – “The Miracle of Science with Soul” – mean?

Dr. Rosen: 100+ years ago, Samuel Golter, one of the founders of City of Hope said: “There is no profit in curing the body if in the process we destroy the soul.” For decades, City of Hope has lived by this credo, providing a comprehensive, compassionate and research-based treatment approach.

“The Miracle of Science with Soul” refers to the lives that we save by uniting science and research with compassionate care.

“Miracle” represents what people with cancer and other deadly diseases say they want most of all.

“Science” speaks to the many innovations we’ve pioneered, which demonstrate that medical miracles happen here.

“Soul” represents our compassionate care. We’re an untraditional health system — and our people, culture and campus reflect this.

 

Can you please describe how City of Hope has evolved throughout its 100-year history from a tuberculosis sanitorium into a world-class research-centered institution? 

Dr. Rosen: City of Hope is a leading comprehensive cancer center and independent biomedical research institution. Over the years, our discoveries have changed the lives of millions of patients around the world.

We pioneered the research leading to the first synthetic insulin and the technology behind numerous cancer-fighting drugs, including Herceptin (trastuzumab), Avasatin (bevacizumab), Erbitux (cetuximab), and Rituxin (rituximab).

As previously mentioned, we hold 300+ patents, have numerous potential therapies in the pipeline at any given time, and treat 1,000+ patients a year in therapeutic clinical trials.

These numbers reflect our commitment to innovation and rapid translation of science into therapies to benefit patients.

We are home to Beckman Research Institute of City of Hope, the first of only five Beckman Research Institutes established by funding from the Arnold and Mabel Beckman Foundation. It is responsible for fundamentally expanding the world’s understanding of how biology affects diseases such as cancer, HIV/AIDS and diabetes.

Recognizing our team’s accomplishments in cancer research, treatment, patient care, education and prevention, the National Cancer Institute has designated City of Hope as a comprehensive cancer center. This is an honor reserved for only 47 institutions nationwide. Our five Cancer Center Research Programs run the gamut from basic and translational studies, to Phase I and II clinical protocols and follow-up studies in survivorship and symptom management.

City of Hope’s Diabetes & Metabolism Research Institute offers a broad diabetes and endocrinology program combining groundbreaking research, unique treatments and comprehensive education to help people with diabetes and other endocrine diseases live longer, better lives.

Our dedicated, multidisciplinary team of healthcare professionals at the Hematologic Malignancies & Stem Cell Institute combine innovative research discoveries with superior clinical treatments to improve outcomes for patients with hematologic cancers.

Working closely with the City of Hope comprehensive cancer center’s Developmental Cancer Therapeutics Program and other cancer centers, the Medical Oncology & Therapeutics Research multidisciplinary program includes basic, translational and clinical research and fosters collaborations among scientists and clinicians.

City of Hope’s Radiation Oncology Department is on the forefront of improving patient care, and our staff is constantly studying new research technologies, clinical trials and treatment methods that can lead to better outcomes and quality of life for our patients.

What attracted you to City of Hope? And how do you define success in your present role as provost and CSO?

Dr. Rosen: Helping cancer patients and their families gives me a sense of purpose. I encourage everyone to find a passion and find an organization that fits their passion. City of Hope is a special place. What we do is bigger than ourselves.

I define success as finding cures and helping patients live stronger, better lives. I am focused on leading a diverse team of scientists, clinicians and administrative leaders committed to discovering breakthroughs and specialized therapies.

COH2 Dr__Steve_Rosen_

Image SOURCE: Photograph of Provost and Chief Scientific Officer Steven T. Rosen, M.D., courtesy of City of Hope, Duarte, California.

 

Steven T. Rosen, M.D.
Provost and Chief Scientific Officer

City of Hope
Duarte, California

Steven T. Rosen, M.D., is provost and chief scientific officer for City of Hope and a member of City of Hope’s Executive Team. He also is director of the Comprehensive Cancer Center and holds the Irell & Manella Cancer Center Director’s Distinguished Chair, and he is director of Beckman Research Institute (BRI) and the Irell & Manella Graduate School of Biological Sciences.

Dr. Rosen sets the scientific direction of City of Hope, shaping the research and educational vision for the biomedical research, treatment and education institution. Working closely and collaboratively with City of Hope’s scientists, clinicians and administrative leaders, he develops strategies that contribute to the organization’s mission.

As director of BRI, he works with faculty across the institution to help shape and direct the scientific vision for BRI while leading the vital basic and translational research that is fundamental to our strategic plan and mission. He focuses on opportunities for expanding and integrating our research initiatives; recruiting and leading talented scientists; helping our talented researchers achieve national and international recognition; and promoting our national standing as a premier scientific organization.

Prior to joining City of Hope, Dr. Rosen was the Genevieve Teuton Professor of Medicine at the Feinberg School of Medicine at Northwestern University in Chicago. He served for 24 years as director of Northwestern’s Robert H. Lurie Comprehensive Cancer Center. Under his leadership, the center received continuous National Cancer Institute (NCI) funding beginning in 1993 and built nationally recognized programs in laboratory sciences, clinical investigations, translational research and cancer prevention and control. The center attained comprehensive status in 1997.

Dr. Rosen has published more than 400 original reports, editorials, books and book chapters. His research has been funded by the National Cancer Institute, American Cancer Society, Leukemia & Lymphoma Society of America and Multiple Myeloma Research Foundation.

Dr. Rosen also has served as an adviser for several of these organizations and on the external advisory boards of more than a dozen NCI-designated Comprehensive Cancer Centers. He is the current editor-in-chief of the textbook series “Cancer Treatment & Research.”

Recognized as one of the Best Doctors in America, Dr. Rosen is a recipient of the Martin Luther King Humanitarian Award from Northwestern Memorial Hospital and the Man of Distinction Award from the Israel Cancer Research Fund. He earned his bachelor’s degree and medical degree with distinction from Northwestern University from which he also earned the Alumni Merit Award, and is a member of the Alpha Omega Alpha Honor Society.

Editor’s Note: 

We would like to thank Mary-Fran Faraji, David Caouette, and Chantal Roshetar of the Communications and Public Affairs department at the City of Hope, for the gracious help and invaluable support they provided during this interview.

 

REFERENCE/SOURCE

The City of Hope (https://www.cityofhope.org/homepage), Duarte, California.

Other related articles

Retrieved from https://www.cityofhope.org/people/rosen-steven

Retrieved from https://www.cityofhope.org/research/beckman-research-institute

Retrieved from https://www.cityofhope.org/research/comprehensive-cancer-center

Retrieved from https://www.cityofhope.org/research/research-overview/diabetes-metabolism-research-institute

Retrieved from https://www.cityofhope.org/patients/departments-and-services/hematologic-malignancies-and-stem-cell-transplantation-institute

Retrieved from https://www.cityofhope.org/patients/departments-and-services/medical-oncology-and-therapeutics-research/medical-oncology-research

Retrieved from https://www.cityofhope.org/patients/cancers-and-treatments/departments-and-services/radiation-oncology/radiation-oncology-research

                        

Other related articles were published in this Open Access Online Scientific Journal include the following: 

2017

Expedite Use of Agents in Clinical Trials: New Drug Formulary Created – The NCI Formulary is a public-private partnership between NCI, part of the National Institutes of Health, and pharmaceutical and biotechnology companies

https://pharmaceuticalintelligence.com/2017/01/12/expedite-use-of-agents-in-clinical-trials-new-drug-formulary-created-the-nci-formulary-is-a-public-private-partnership-between-nci-part-of-the-national-institutes-of-health-and-pharmaceutical-and/

The top 15 best-selling cancer drugs in 2022 & Projected Sales in 2020 of World’s Top Ten Oncology Drugs

https://pharmaceuticalintelligence.com/2017/01/03/projected-sales-in-2020-of-worlds-top-ten-oncology-drugs/

2016

Funding Opportunities for Cancer Research

https://pharmaceuticalintelligence.com/2016/12/08/funding-opportunities-for-cancer-research/

Recent Breakthroughs in Cancer Research at the Technion-Israel Institute of Technology- 2015

https://pharmaceuticalintelligence.com/2016/02/03/recent-breakthroughs-in-cancer-research-at-the-technion-israel-institute-of-technology-2015/

New York Times Articles on Cancer Immunotherapy and Cancer Treatment Options

https://pharmaceuticalintelligence.com/2016/08/09/new-york-times-articles-on-immunotherapy-and-cancer-treatment-options/

  • Cancer Biology & Genomics for Disease Diagnosis, on Amazon since 8/11/2015

http://www.amazon.com/dp/B013RVYR2K

https://pharmaceuticalintelligence.com/biomed-e-books/series-c-e-books-on-cancer-oncology/volume-2-immunotherapy-in-oncology/

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CD-4 Therapy for Solid Tumors

Curator: Larry H. Bernstein, MD, FCAP

 

CD4 T-cell Immunotherapy Shows Activity in Solid Tumors

Alexander M. Castellino, PhD

http://www.medscape.com/viewarticle/862095

For the first time, treatment with genetically engineered T-cells has used CD4 T-cells instead of the CD8 T-cells, which are used in the chimeric antigen receptor (CAR) T-cell approach. Early data suggest that this CD4 T-cell approach has activity against solid tumors, whereas the CAR T-cell approach so far has achieved dramatic success in hematologic malignancies.

In the new approach, CD4 T-cells were genetically engineered to target MAGE-A3, a protein found on many tumor cells. The treatment was found to be safe in patients with metastatic cancers, according to data from a phase 1 clinical study presented here at the American Association for Cancer Research (AACR) 2016 Annual Meeting.

“This is the first trial testing an immunotherapy using genetically engineered CD4 T-cells,” senior author Steven A. Rosenberg, MD, PhD, chief of the Surgery Branch at the National Cancer Institute (NCI), told Medscape Medical News.

Most approaches use CD8 T-cells. Although CD8 T-cells are known be cytotoxic and CD4 T-cells are normally considered helper cells, CD4 T-cells can induce tumor regression, he said.

Louis M. Weiner, MD, director of the Lombardi Comprehensive Cancer Center at Georgetown University, in Washington, DC, indicated that in contrast with CAR T-cells, these CD4 T-cells target proteins on solid tumors. “CAR T-cells are not tumor specific and do not target solid tumors,” he said.

Engineering CD4 Cells

Immunotherapy with engineered CD4 T-cells was personalized for each patient whose tumors had not responded to or had recurred following treatment with least one standard therapy. The immunotherapy was specific for patients in whom a specific human leukocyte antigen (HLA) — HLA-DPB1*0401 — was found to be expressed on their cells and whose tumors expressed MAGE-A3.

MAGE-A3 belongs to a class of proteins expressed during fetal development. The expression is lost in normal adult tissue but is reexpressed on tumor cells, explained presenter Yong-Chen William Lu, PhD, a research fellow in the Surgery Branch of the NCI.

Targeting MAGE-A3 is relevant, because it is frequently expressed in a variety of cancers, such as melanoma and urothelial, esophageal, and cervical cancers, he pointed out.

 Researchers purified CD4 T-cells from the peripheral blood of patients. Next, the CD4 T-cells were genetically engineered with a retrovirus carrying the T-cell receptor (TCR) gene that recognizes MAGE-A3. The modified cells were grown ex vivo and were transferred back into the patient.

Clinical Results

Dr Lu presented data for 14 patients enrolled into the study: eight patients received cell doses from 10 million to 30 billion cells, and six patients received up to 100 billion cells.

This was similar to a phase 1 dose-finding study, except the researchers were seeking to determine the maximum number of genetically engineered CD4 T-cells that a patient could safely receive.

One patient with metastatic cervical cancer, another with metastatic esophageal cancer, and a third with metastatic urothelial cancer experienced partial objective responses. At 15 months, the response is ongoing in the patient with cervical cancer; after 7 months of treatment, the response was durable in the patient with urothelial cancer; and a response lasting 4 months was reported for the patient with esophageal cancer.

Dr Lu said that a phase 2 trial has been initiated to study the clinical responses of this T-cell receptor therapy in different types of metastatic cancers.

In his discussion of the paper, Michel Sadelain, MD, of the Memorial Sloan Kettering Cancer Center, New York City, said, “Although therapy with CD4 cells has been evaluated using endogenous receptor, this is the first study using genetically engineered CD4 T-cells.”

Although the study showed that therapy with genetically engineered T-cells is safe and efficacious at least in three patients, the mechanism of cytotoxicity remains unclear, Dr Sadelain indicated.

Comparison With CAR T-cells

CAR T-cells act in much the same way. CARs are chimeric antigen receptors that have an antigen-recognition domain of an antibody (the V region) and a “business end,” which activates T-cells. In this case, CD8 T-cells from the patients are used to genetically engineer T-cells ex vivo. In the majority of cases, dramatic responses have been seen in hematologic malignancies.

CARs, directed against self-proteins, result in on-target, off-tumor effects, Gregory L. Beatty, MD, PhD, assistant professor of medicine at the University of Pennsylvania, in Philadelphia, indicated when he reported the first success story of CAR T-cells in a solid pancreatic cancer tumor.

Side effects of therapy with CD4 T-cells targeting MAGE-A3 were different and similar to side effects of chemotherapy, because patients received a lymphodepleting regimen of cyclophosphamide and fludabarine. Toxicities included high fever, which was experienced by the majority of patients (12/14). The fever lasted 1 to 2 weeks and was easily manageable.

High levels of the cytokine interleukin-6 (IL-6) were detected in the serum of all patients after treatment. However, the elevation in IL-6 levels was not considered to be a cytokine release syndrome, because no side effects occurred that correlated with the syndrome, Dr Liu indicated.

He also indicated that future studies are planned that will employ genetically engineered CD4 T-cells in combination with programmed cell death protein 1–blocking antibodies.

This study was funded by Intramural Research Program of the National Institutes of Health. The NCI’s research and development of T-cell receptor therapy targeting MAGE-A3 are supported in part under a cooperative research and development agreement between the NCI and Kite Pharma, Inc. Kite has an exclusive, worldwide license with the NIH for intellectual property relating to retrovirally transduced HLA-DPB1*0401 and HLA A1 T-cell receptor therapy targeting MAGE-A3 antigen. Dr Lu and Dr Rosenberg have disclosed no relevant financial relationships.

American Association for Cancer Research (AACR) 2016 Annual Meeting: Abstract CT003, presented April 17, 2016.

 

Searches Related to immunotherapy using genetically engineered CD4 T-cells

 

Genetic engineering of T cells for adoptive immunotherapy

To be effective for the treatment of cancer and infectious diseases, T cell adoptive immunotherapy requires large numbers of cells with abundant proliferative reserves and intact effector functions. We are achieving these goals using a gene therapy strategy wherein the desired characteristics are introduced into a starting cell population, primarily by high efficiency lentiviral vector-mediated transduction. Modified cells are then expanded using ex vivo expansion protocols designed to minimally alter the desired cellular phenotype. In this article, we focus on strategies to (1) dissect the signals controlling T cell proliferation; (2) render CD4 T cells resistant to HIV-1 infection; and (3) redirect CD8 T cell antigen specificity.
Adoptive T cell therapy is a form of transfusion therapy involving the infusion of large numbers of T cells with the aim of eliminating, or at least controlling, malignancies or infectious diseases. Successful applications of this technique include the infusion of CMV-or EBVspecific CTLs to protect immunosuppressed patients from these transplantation-associated diseases [1,2]. Furthermore, donor lymphocyte infusions of ex vivo-expanded allogeneic T cells have been used to successfully treat hematological malignancies in patients with relapsed disease following allogeneic hematopoietic stem cell transplant [3]. However, in many other malignancies and chronic viral infections such as HIV-1, adoptive T cell therapy has achieved inconsistent and/or marginal successes. Nevertheless, there are compelling reasons for optimism on this strategy. For example, the existence of HIV-positive elite non-progressors [4], as well as the correlation between the presence of intratumoral T cells and a favorable prognosis in malignancies such as ovarian [5,6] and colon carcinoma [7,8], provides in vivo evidence for the critical role of the immune system in controlling both HIV and cancer.
The key to successful adoptive immunotherapy strategies appears to consist of (1) using the “right” T cell type(s) and (2) obtaining therapeutically effective numbers of these cells without compromising their effector functions or their ability to engraft within the host. This article is focused on strategies employed in our laboratory to generate the “right” cell through genetic engineering approaches, with an emphasis on redirecting the antigen specificity of CD8 T cells, and rendering CD4 T cells resistant to HIV-1 infection. The article by Paulos et al. describes the evolving process of how to best obtain therapeutically effective numbers of the “right” cells by optimizing ex vivo cell expansion strategies.
Our laboratory’s overall strategy and flow plan for development and evaluation of engineered T cells is depicted in Fig. 1. We work almost exclusively with primary human T cells; little or no work is performed with conventional established cell lines. Thus, we benefit substantially from our close association with the UPenn Human Immunology Core. The Core performs leukaphereses on healthy donors 2–3 times a week, and provides purified peripheral blood mononuclear cell subsets, ensuring a constant influx of fresh human T cells into our laboratory. We have extensive experience in developing both bead- and cell-based artificial antigen presenting cells (aAPCs), as described in detail in the article by Paulos et al. The ability to genetically modify T cells at high efficiency is critical for virtually every project within the laboratory. We have adapted the lentiviral vector system described by Dull [15] for most, but not all, of the engineering applications in our laboratory.
CD4 T cells are the primary target of HIV-1, and decreasing CD4 T cell numbers is a hallmark of advancing HIV-1 disease [34]. Thus, strategies that protect CD4 T cells from HIV-1 infection in vivo would conceivably provide sufficient immunological help to control HIV-1 infection. Our early observations that CD3/CD28 costimulation resulted in improved ex vivo expansion of CD4 T cells from both healthy and HIV-infected donors, as well as enhanced resistance to HIV-1 infection [35,36], ultimately led to the first-in-human trial of lentiviral vector-modified CD4 T cells [37]. In this trial, CD4 T cells from HIV-positive subjects who had failed antiretroviral therapy were transduced with a lentiviral vector encoding an antisense RNA that targeted a 937 bp region in the HIV-1 envelope gene. Preclinical studies demonstrated that this antisense region, directed against the HIV-1NL4-3 envelope, provided robust protection from a broad range of both R5-and X4-tropic HIV-1 isolates [38]. One year after administration of a single dose of the gene-modified cells, four of the five enrolled patients had increased peripheral blood CD4 T cell counts, and in one subject, a 1.7 log decrease in viral load was observed. Finally, in two of the five patients, persistence of the gene-modified cells was detected one year post-infusion.
Since its identification as the primary co-receptor involved in HIV transmission, CCR5 has attracted considerable attention as a target for HIV therapy [42,43]. Indeed, “experiments of nature” have shown that individuals with a homozygous CCR5 Δ32 deletion are highly resistant to HIV-1 infection. Thus, we hypothesized that knocking out the CCR5 locus would generate CD4 T cells permanently resistant to infection by R5 isolates of HIV-1. To test this hypothesis we took advantage of zinc-finger nuclease (ZFN) technology [44]. ZFNs introduce sequencespecific double-strand DNA breakage, which is imperfectly repaired by non-homologous endjoining. This results in the permanent disruption of the genomic target, a process termed genome editing (Fig. 3).
Genetic modification of T cells to redirect antigen specificity is an attractive strategy compared to the lengthy process of growing T cell lines or CTL clones for adoptive transfer. Genetically modified, adoptively transferred T cells are capable of long-term persistence in humans [37, 46,47], demonstrating the feasibility of this approach. When compared to the months it can take to generate an infusion dose of antigen-specific CTL lines or clones from a patient, a homogeneous population of redirected antigen-specific cells can be expanded to therapeutically relevant numbers in about two weeks [3]. Several strategies are being explored to bypass the need to expand antigen-specific T cells for adoptive T cell therapy. The approaches currently studied in our laboratory involve the genetic transfer of chimeric antigen receptors and supraphysiologic T cell receptors.
Chimeric antigen receptors (CARs or T-bodies) are artificial T cell receptors that combine the extracellular single-chain variable fragment (scFv) of an antibody with intracellular signaling domains, such as CD3ζ or Fc(ε)RIγ [48–50]. When expressed on T cells, the receptor bypasses the need for antigen presentation on MHC since the scFv binds directly to cell surface antigens. This is an important feature, since many tumors and virus-infected cells downregulate MHCI, rendering them invisible to the adaptive immune system. The high-affinity nature of the scFv domain makes these engineered T cells highly sensitive to low antigen densities. In addition, new chimeric antigen receptors are relatively easy to produce from hybridomas. The key to this approach is the identification of antigens with high surface expression on tumor cells, but reduced or absent expression on normal tissues.  Since one can redirect both CD4 and CD8 T cells, the T-body approach to immunotherapy represents a near universal “off the shelf” method to generate large numbers of antigen-specific helper and cytotoxic T cells.
Many T-bodies targeting diverse tumors have been developed [51], and four have been evaluated clinically [52–55]. Three of the four studies were characterized by poor transgene expression and limited T-body engraftment. However, in a study of metastatic renal cell carcinoma using a T-body directed against carbonic anhydrase IX [55], T-body-expressing cells were detectable in the peripheral blood for nearly 2 months post-administration.
The major goals in the T-body field currently are to optimize their engraftment and maximize their effector functions. Our laboratory is addressing both problems simultaneously through an in-depth study of the requirements for T-body activation. We hypothesize that their limited persistence is due to incomplete cell activation due to the lack of costimulation. While naïve T cells depend on costimulation through CD28 ligation to avoid anergy and undergo full activation in response to antigen, it is recognized that effector cells also require costimulation to properly proliferate and produce cytokines [56]. Previous studies have shown that providing CD28 costimulation is crucial for the antitumoral function of adoptively transferred T cells and T-bodies [57–59]. Unlike conventional T cell activation, which requires two discrete signals, T-bodies can be engineered to provide both costimulation and CD3 signaling through one binding event.
A different approach for redirecting specificity to T cells for adoptive immunotherapy involves the genetic transfer of full-length TCR genes. A T cell’s specificity for its cognate antigen is solely determined by its TCR. Genes encoding the α and β chains of a T cell receptor (TCR) can be isolated from a T cell specific for the antigen of interest and restricted to a defined HLA allele, inserted into a vector, and then introduced into large numbers of T cells of individual patients that share the restricting HLA allele as well as the targeted antigen. In 1999, Clay and colleagues from Rosenberg’s group at the National Cancer Institute were the first to report the transfer of TCR genes via a retroviral vector into human lymphocytes and to show that T cells gained stable reactivity to MART-1 [67]. To date, many others have shown that the same approach can be used to transfer specificity for multiple viral and tumor associated antigens in mice and human systems. These T cells gain effector functions against the transferred TCR’s cognate antigen, as defined by proliferation, cytokine production, lysis of targets presenting the antigen, trafficking to tumor sites in vivo, and clearance of tumors and viral infection.
In 2006, Rosenberg’s group redirected patients’ PBLs with the naturally occurring, MART-1- specific TCR reported in 1999 by Clay. In the first clinical trial to test TCR-transfer immunotherapy, these modified T cells were infused into melanoma patients [68]. While the transduced T cells persisted in vivo, only two of the 17 patients had an objective response to this therapy. One issue revealed by the study was the poor expression of the transgenic TCRs by the transferred T cells. Nonetheless, the results from this trial showed the potential of TCR transfer immunotherapy as a safe form of therapy for cancer and highlighted the need to optimize such therapy to attain maximum potency.
The adoptive immunotherapy field is advancing by a tried-and-true method: learning from disappointments and moving forward. Our ability to fully realize the therapeutic potential of adoptive T cell therapy is tied to a more complete understanding of how human T cells receive signals, kill targets, and modulate effective immune responses. Our goal is to perform labbased experiments that provide insight into how primary T cells function in a manner that will facilitate and enable adoptive T cell therapy clinical trials. Our ability to efficiently modify (and expand) T cells ex vivo provides the opportunity to deliver sufficient immune firepower where it has heretofore been lacking. Sustained transgene expression, coupled with enhanced in vivo engraftment capability, will move adoptive immunotherapy into a realm where longterm therapeutic benefits are the norm rather than the exception.
Genetic Modification of T Lymphocytes for Adoptive Immunotherapy

Claudia Rossig1 and Malcolm K. Brenner2
Molecular Therapy (2004) 10, 5–18;   http://dx.doi.org:/10.1016/j.ymthe.2004.04.014      http://www.nature.com/mt/journal/v10/n1/full/mt20041193a.html

Adoptive transfer of T lymphocytes is a promising therapy for malignancies—particularly of the hemopoietic system—and for otherwise intractable viral diseases. Efforts to broaden the approach have been limited by the physiology of the T cells themselves and by a range of immune evasion mechanisms developed by tumor cells. In this review we show how genetic modification of T cells is being used preclinically and in patients to overcome these limitations, by incorporation of novel receptors, resistance mechanisms, and control genes. We also discuss how the increasing safety and effectiveness of gene transfer technologies will lead to an increase in the use of gene-modified T cells for the treatment of a wider range of disorders.

That gene transfer could be used to improve the effectiveness of T lymphocytes was apparent from the beginning of clinical studies in the field. T cells were the very first targets for genetic modification in human gene transfer experiments. Rosenberg’s group marked tumor-infiltrating lymphocytes ex vivo with a Moloney retroviral vector encoding neomycin phosphotransferase before reinfusing them and attempting to demonstrate selective accumulation at tumor sites. Shortly thereafter, Blaese and Anderson led a group that infused corrected T cells into two children with severe combined immunodeficiency due to ADA deficiency. While neither study was completely successful in terms of outcome, both showed the feasibility of ex vivo gene transfer into human cells and set the stage for many of the studies that followed. More recently, a second wave of interest in adoptive T cell therapies has developed, based on their success in the prevention and treatment of viral infections such as EBV and cytomegalovirus (CMV) and on their apparent ability to eradicate hematologic and perhaps solid malignancies1,2,3,4,5,6. There has been a corresponding increase in studies directed toward enhancing the antineoplastic and antiviral properties of the T cells. In this article we will review how gene transfer may be used to produce the desired improvements focusing on vectors and genes that have had clinical application.

Currently available viral and nonviral vector systems lack a pattern of biodistribution that would favor T cell transduction in vivo—as occurs, for example, with adenovectors and the liver or liposomal vectors and the lung. This lack of favorable biodistribution cannot yet be compensated for by the introduction of specific T-cell-targeting ligands into vectors. Hence, all T cell gene transfer studies conducted to date have used ex vivo transduction followed by adoptive transfer of gene-modified cells. This approach is inherently less attractive for commercial development than directin vivo gene transfer and has probably restricted interest in developing clinical applications using these cells. On the other hand, ex vivo transduction may be more readily controlled, characterized, and standardized than in vivo efforts and may ultimately produce a better defined final product (the transduced cell).

The gene products of suicide and coexpressed resistance genes are highly immunogenic and may induce immune-mediated rejection of the transduced cells. In one study, the persistence of adoptively transferred autologous CD8+ HIV-specific CTL clones modified to express the hygromycin phosphotransferase (Hy) gene and the herpesvirus thymidine kinase gene as a fusion gene was limited by the induction of a potent CD8+ class I MHC-restricted CTL response specific for epitopes derived from the Hy-tk protein126. Less immunogenic suicide and selection marker genes, preferably of human origin, may reduce the immunological inactivation of genetically modified donor lymphocytes. Human-derived prodrug-activating systems include the human folylpolyglutamate synthetase/methotrexate127, the deoxycytidine/cytosine arabinoside128, or the carboxylesterase/irinotecan129 systems. These systems do not activate nontoxic prodrugs but are based on enhancement of already potent chemotherapeutic agents. The administration of methotrexate to treat severe GVHD may not only kill transduced donor lymphocytes but may also have additional inhibitory activity on nontransduced but activated T cells.

Finally, endogenous proapoptotic molecules have been proposed as nonimmunogenic suicide genes. A chimeric protein that contains the FK506-binding protein FKBP12 linked to the intracellular domain of human Fas130 was recently introduced. Addition of the dimerizing prodrug induces Fas crosslinking with subsequent triggering of an apoptotic death signal.

Genetic engineering of T lymphocytes should help deliver on the promise of immunotherapies for cancer, infection, and autoimmune disease. Improvements in transduction, selection, and expansion techniques and the development of new viral vectors incapable of insertional mutagenesis will reduce the risks and further enhance the integration of T cell and gene therapies. Nonetheless, successful application of the proposed modifications to the clinical setting still requires many iterative studies to allow investigators to optimize the individual components of the approach.

Genetically modified T cells in cancer therapy: opportunities and challenges
Michaela Sharpe, Natalie Mount

 

The feasibility of T-cell adoptive transfer was first reported nearly 20 years ago (Walter et al., 1995) and the field of T-cell therapies is now poised for significant clinical advances. Recent clinical trial successes have been achieved through multiple small advances, improved understanding of immunology and emerging technologies. As the key challenges of T-cell avidity, persistence and ability to exert the desired anti-tumour effects as well as the identification of new target antigens are addressed, a broader clinical application of these therapies could be achieved. As the clinical data emerges, the challenge of making these therapies available to patients shifts to implementing robust, scalable and cost-effective manufacture and to the further evolution of the regulatory requirements to ensure an appropriate but proportionate system that is adapted to the characteristics of these innovative new medicines.

 

 

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A Mechanism of Cancer Metastasis

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

A Protein that Spreads Cancer

Nils Halberg at the University of Bergen has identified a protein that makes it possible for cancer cells to spread

http://www.technologynetworks.com/Proteomics/news.aspx?ID=190563

The cells inside a tumour differ a lot. While some remains “good” and do not cause trouble, others become aggressive and starts to spread to other organ sites. It is very hard to predict which cells become aggressive or not.

Nevertheless, by isolating these aggressive cancer cells in in vivotests on animals, Nils Halberg at the Department of Biomedicinet the University of Bergen (UiB) and the researchers Dr. Sohail Tavazoie and Dr. Caitlin Sengelaub at The Rockefeller University have discovered a certain protein (PITPNC1) that characterise aggressive cancer cells.

“We discovered that the aggressive cancer cells that are spreading in colon, breast, and skin cancer contained a much higher portion of the protein PITPNC1, than the non-aggressive cancer cells,” says researcher Nils Halberg of the CELLNET Group at the Department of Biomedicine at UiB.

“This means we can predict which of the cancer cells are getting aggressive and spread, at a much earlier stage than today.”

How cells penetrate tissue

The researcher also discovered that this protein, that characterizes the aggressive cancer cells, has got a very specific function in the process of spreading cancer.

The cancer cells spread from one place in the body to another, through the blood vessel. To get into the blood vessels, the cell needs to penetrate tissue, both when it leaves the tumour and when it is attaching to a new organ.

“The protein PITPNC1 regulates a process whereby the cancer cells are secreting molecules, which cut through a network of proteins outside the cells, like scissors. The cancer cell is then able to penetrate the tissue and set up a colonies at new organ sites,” Halberg explains.

Custom-made therapy

A tumour that is not spreading, is usually not dangerous for the patient if it is removed. The hard part in cancer therapy is when the tumour starts to spread. Guided by the new discoveries, supported by the Bergen Research Foundation´s (BFS) Recruitment Programme, Halberg hopes to contribute to a better treatment of cancer patients.

“If we get to the point where we can offer a custom-made therapy that targets the function of this protein, we might be able to stop it spreading,” says Nils Halberg.

 

RDGBB; RDGBB1; MRDGBbeta; RDGB-BETA; M-RDGB-beta

This gene encodes a member of the phosphatidylinositol transfer protein family. The encoded cytoplasmic protein plays a role in multiple processes including cell signaling and lipid metabolism by facilitating the transfer of phosphatidylinositol between membrane compartments. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene, and a pseudogene of this gene is located on the long arm of chromosome 1. [provided by RefSeq, May 2012]

 

Phosphatidylinositol Transfer Protein, Cytoplasmic 1 (PITPNC1) Binds and Transfers Phosphatidic Acid*

Kathryn Garner‡ , Alan N. Hunt§ , Grielof Koster§ , Pentti Somerharju¶ , Emily Groves‡1, Michelle Li‡ , Padinjat Raghu , Roman Holic‡ , and Shamshad Cockcroft‡2
JBC Papers in Press, July 21, 2012,      http://dx.doi.org:/10.1074/jbc.M112.375840

Background: Phosphatidylinositol transfer protein, cytoplasmic 1 (PITPNC1) (alternative name, RdgB) promotes metastatic colonization and angiogenesis in humans.

Results: We demonstrate that RdgB is a phosphatidic acid (PA)- and phosphatidylinositol-binding protein and binds PA derived from the phospholipase D pathway.

Conclusion: RdgB is the first lipid-binding protein identified that can bind and transfer PA.

Significance: PA bound to RdgB is a likely effector downstream of phospholipase D

 

PITPNC1 Recruits RAB1B to the Golgi Network to Drive Malignant Secretion

Nils Halberg3,4,, Caitlin A. Sengelaub3, Kristina Navrazhina, Henrik Molina, Kunihiro Uryu, Sohail F. Tavazoie
Cancer Cell 14 Mar 2016; Volume 29, Issue 3:339–353   http://dx.doi.org/10.1016/j.ccell.2016.02.013
Highlights
  • PITPNC1 promotes metastasis by melanoma, breast cancer, and colon cancer cells
  • PITPNC1 recruits RAB1B to the Golgi compartment of the cell
  • Golgi localization of RAB1B enhances vesicular secretion via GOLPH3 recruitment

Summary

Enhanced secretion of tumorigenic effector proteins is a feature of malignant cells. The molecular mechanisms underlying this feature are poorly defined. We identify PITPNC1 as a gene amplified in a large fraction of human breast cancer and overexpressed in metastatic breast, melanoma, and colon cancers. Biochemical, molecular, and cell-biological studies reveal that PITPNC1 promotes malignant secretion by binding Golgi-resident PI4P and localizing RAB1B to the Golgi. RAB1B localization to the Golgi allows for the recruitment of GOLPH3, which facilitates Golgi extension and enhanced vesicular release. PITPNC1-mediated vesicular release drives metastasis by increasing the secretion of pro-invasive and pro-angiogenic mediators HTRA1, MMP1, FAM3C, PDGFA, and ADAM10. We establish PITPNC1 as a PI4P-binding protein that enhances vesicular secretion capacity in malignancy.

 

 

Cancerous Conduits

Metastatic cancer cells use nanotubes to manipulate blood vessels.

By Amanda B. Keener | April 1, 2016

http://www.the-scientist.com/?articles.view/articleNo/45579/title/Cancerous-Conduits

MAKING CONTACT: Breast cancer cells (white arrows) in culture deliver microRNAs to endothelial cells through filamentous nanotubes (yellow arrow).
LABORATORY OF SHILADITYA SENGUPTA

 

EDITOR’S CHOICE IN CELL & MOLECULAR BIOLOGY

The paper
Y. Conner et al., “Physical nanoscale conduit-mediated communication between tumour cells and the endothelium modulates endothelial phenotype,” Nat Commun, 6:8671, 2015.

Branching Out
Harvard bioengineer Shiladitya Sengupta and his team were establishing a culture system to model the matrix and blood vessel networks that surround tumors when they found that human breast cancer cells spread out along blood vessel endothelial cells rather than form spheroid tumors as expected. Taking a closer look using scanning electron microscopy, they spied nanoscale filaments consisting of membrane and cytoskeletal components linking the two cell types.

Manipulative Metastases
These cancer cell–spawned nanotubes, the team discovered, could transfer a dye from cancer cells to endothelial cells both in culture and in a mouse model of breast cancer metastasis to the lungs.The cells also transferred microRNAs known to regulate endothelial cell adhesion and disassociation of tight junctions, which Sengupta speculates may help cancer cells slip in and out of blood vessels. This study is the first to suggest a role for nanotubes in metastasis.

Breaking the Chain
Sengupta’s team then used low doses of cytoskeleton-disrupting drugs to block nanotube formation. Emil Lou, an oncologist at the University of Minnesota who studies nanotubes in cancer and was not involved in the study, says this approach is a “good start,” though such drugs would not be used in human patients because they are not specific to nanotubes.

In the Details
Lou says the study emphasizes the importance of understanding interactions between tumors and their surrounding tissues on a molecular level. Going forward, Sengupta plans to study how the tubes are formed in melanoma as well as breast and ovarian cancers to try to identify other drug targets.

 

Physical nanoscale conduit-mediated communication between tumour cells and the endothelium modulates endothelial phenotype

Yamicia ConnorSarah TekleabShyama NandakumarCherelle Walls,….., Bruce ZetterElazer R. Edelman & Shiladitya Sengupta
Nature Communications6,Article number:8671
    
          doi:10.1038/ncomms9671

Metastasis is a major cause of mortality and remains a hurdle in the search for a cure for cancer. Not much is known about metastatic cancer cells and endothelial cross-talk, which occurs at multiple stages during metastasis. Here we report a dynamic regulation of the endothelium by cancer cells through the formation of nanoscale intercellular membrane bridges, which act as physical conduits for transfer of microRNAs. The communication between the tumour cell and the endothelium upregulates markers associated with pathological endothelium, which is reversed by pharmacological inhibition of these nanoscale conduits. These results lead us to define the notion of ‘metastatic hijack’: cancer cell-induced transformation of healthy endothelium into pathological endothelium via horizontal communication through the nanoscale conduits. Pharmacological perturbation of these nanoscale membrane bridges decreases metastatic foci in vivo. Targeting these nanoscale membrane bridges may potentially emerge as a new therapeutic opportunity in the management of metastatic cancer.

 

Metastasis is the culmination of a cascade of events, including invasion and intravasation of tumour cells, survival in circulation, extravasation and metastatic colonization4. Multiple studies have reported a dynamic interaction between the metastatic tumour cell and the target organ, mediated by cytokines4, 12 or by exosomes that can prime metastasis by creating a pre-metastatic niche13. Interestingly, the interactions between cancer cells and endothelium in the context of metastasis, which occurs during intravasation, circulation and extravasation, remains less studied. Cancer cell-secreted soluble factors can induce retraction of endothelial cells and the subsequent attachment and transmigration of tumour cells through the endothelial monolayers14, 15. Recently, studies indicate a more intricate communication between cancer cells and the endothelium. For example, a miRNA regulon was found to mediate endothelial recruitment and metastasis by cancer cells16. Similarly, exosome-mediated transfer of cancer-secreted miR-105 was recently reported to disrupt the endothelial barrier and promote metastasis17. We rationalized that a better understanding of cancer–endothelial intercellular communication, primarily during extravasation, could lead to novel strategies for inhibiting metastasis18.

Recently, nanoscale membrane bridges, such as tunnelling nanotubes (TNTs) and filopodias, have emerged as a novel mechanism of intercellular communication19. For example, specialized signalling filopodia or cytonemes were recently shown to transport morphogens during development20. Similarly, TNTs, which unlike filopodia have no contact with the substratum21, were shown to facilitate HIV-1 transmission between T cells, enable the spread of calcium-mediated signal between cells and transfer p-glycoproteins conferring multi-drug resistance between cancer cells22, 23, 24, 25. TNTs were also recently implicated in trafficking of mitochondria from endothelial to cancer cells and transfer miRNA between osteosarcoma cells and stromal murine osteoblast cells, and between smooth muscle cells and the endothelium26, 27, 28. However, whether similar intercellular nanostructure-mediated communication can be harnessed by cancer cells to modulate the endothelium is not known.

Here we report that metastatic cancer cells preferentially form nanoscale intercellular membrane bridges with endothelial cells. These nanoscale bridges act as physical conduits through which the cancer cells can horizontally transfer miRNA to the endothelium. We observe that the recipient endothelial cells present an miRNA profile that is distinct from non-recipient endothelial cells isolated from the same microenvironment. Furthermore, the co-cultures of cancer and endothelial cells upregulate markers associated with pathological endothelium, which is inhibited by pharmacological disruption of the nanoscale conduits. Additionally, the pharmacological inhibitors of these nanoscale conduits can decrease metastatic foci in vivo, which suggests that these nanoscale conduits may potentially emerge as new targets in the management of metastatic cancer.

 

Figure 1: Nanoscale structures physically connect metastatic cells and the endothelium

Nanoscale structures physically connect metastatic cells and the endothelium.

(a) Representative image of MDA-MB-231 cancer cells exhibiting an invasive phenotype in the presence of preformed endothelial tubes in co-culture. (b) Representative image of a mammosphere typically formed by MDA-MB-231 cells when cultured on 3D tumour matrix in the absence of endothelial cells. MDA-MB-231 cells were loaded with CFSE. Actin was labelled with rhodamine phalloidin and nuclei were counterstained with DAPI. (c) A representative SEM of epithelial (EPI) MDA-MB-231 cells aligning on HUVEC (ENDO) tubules in the co-culture. Lower panel shows higher magnification. (d) SEM image reveals nanoscale membrane bridges connecting (nCs) metastatic breast cancer (EPI) cells and endothelial vessels (arrows). (e) A representative transmission electron micrograph shows intercellular connectivity through the nanoscale membrane bridge between MDA-MB-231 and an endothelial cell. (f) A cartoon represents the types of homotypic and heterotypic intercellular nanoscale connections that an epithelial cell may form in the presence of endothelial tubules. Highly metastatic (MDA-MB-468, MDA-MB-231 or MDA-MB-435) or low metastatic (MCF7 and SkBr3) cancer cells were co-cultured with the endothelial tubes. Normal HMECs were used as control. Graphs show percentage of total population of epithelial cells that exhibit either homotyptic (Epi–Epi) or heterotypic (Epi–Endo) nanoscale connections and (g) average number of nanoscale connections formed per cell. Quantification analysis was done on >300 cells of each cell type. Data shown are mean±s.e.m. (n=6 replicates per study, with 2–3 independent experiments). **P<0.01, ***P<0.001 (analysis of variance followed by Bonferroni’s post-hoctest).

The nanoscale bridges are composed of cytoskeletal elements

Figure 3: Structure and function of the heterotypic intercellular nanoscale membrane bridges.

a) Representative images show the heterotypic nanoscale membrane bridges are composed of both F-actin and α/β-tubulin cytoskeletal components. Co-cultures were stained with α/β-tubulin antibody (green) and phalloidin (purple) to label actin, and counterstained with DAPI (nuclear)+WGA (plasma membrane) (blue). Endothelial cells were labelled with DiL-Ac-LDL (red). (b) Mathematical modelling of the structure of the nanoscale connections. The physical properties of actin filaments necessitate microtubules for projections of certain length scales. The maximum projection length for a given minimum diameter at the buckling limit is plotted for actin-only nanoscale structures (purple line). This curve is overlaid with the experimental length and diameter measurements (red dots) from the observed thin projections measured in these studies. Projections containing only actin or projections containing both actin and tubulin can exist to the right of the curve (purple line). However, actin-only projections cannot exist to the left of the curve (green region). (c) The effect of incorporating tubulin in these projections. The maximum length is plotted against the minimum diameter for varying fractions of tubulin incorporated in the nanoscale projection. Addition of microtubules to the projections increases the overall flexural rigidity, shifting the curves left of the actin-only limit (purple line), thus allowing for longer and thinner nanoscale connections. However, owing to the larger radius of microtubules (4 × radius of actin filaments), there is an optimal fraction of tubulin (green line) that can be incorporated into the projection before the effect is reversed. (d) The optimal fraction of microtubules is about 6.6% (red dashed line) to maximize nanostructure flexural strength, while minimizing thickness. (e) Representative confocal image shows the presence of myosin V motor proteins within the intercellular nanostructure (inset shows higher magnification). Scale bar 10μm.

Nanoscale bridges act as conduits for communication

Figure 4: The nanoscale membrane bridges act as conduits for intercellular communication between cancer and endothelial cells.

(a) Confocal image of nanoscale membrane bridge-mediated transfer of cytoplasmic contents. CFSE (green)-loaded MDA-MB-231 cells were co-cultured with the Dil-Ac-LDL (red)-labelled HUVECs. Transfer of the CFSE dye was observed after 24-h co-culture. CFSE dye can be seen within HUVEC cells (yellow arrow). Tumour cells can form a nanobridge with a distal endothelial cell (EC1) than an endothelial cell (EC2) in close proximity. (b,c) Cartoon shows the experimental design, where dual cultures control for vesicle-mediated intercellular transfer. FACS plot show gating for sorting endothelial cells from the co-cultures using dual staining for DiI-Ac-LDL and PECAM-1, and then quantification for CFSE transfer in the isolated endothelial cells. (d) Graph shows quantification of FACS analysis, highlighting increased transfer of CFSE to endothelial cells in the co-culture. (N>100,000 events, n=36 replicates, 3 replicates per study). (e) Graph shows the temporal kinetics of nanoscale connection-mediated intercellular transfer of CFSE from MDA-MB-231 cells to the endothelium (n=2 studies, 3 replicates per study). (f) Effect of small molecule inhibitors of cytoskeletal components on membrane nanobridges. (g) Graphs show treatment with vehicle (control) or a low-dose combination of docetaxel and cytochalasin do not affect the exosome shedding (n=2 independent studies). (h,i) Graphs show the effect of pharmacological inhibitors on the formation of heterotypic and homotypic nanoscale bridges (arrows). (n=2 studies, 6 replicates per study). (j) Graph shows the effect of pharmacological inhibitors on intercellular transfer of CFSE to endothelial cells from cancer cells (n=10 studies, 3 replicates per study). Data shown are mean±s.e.m. (*P<0.05,**P<0.01, ****P<0.001, analysis of variance followed by Bonferroni’s post-hoc test).

Effect of pharmacological inhibition of nanoscale bridges

Nanobridges transfer miRNA from cancer cells to endothelium

Figure 5: The nanoscale membrane bridges act as conduits for intercellular transfer of miRNA between cancer and endothelial cells.

Representative confocal images show the transfer of Cy3-labelled miRNA from MDA-MB-231 cells (EPI) to endothelial cells (ENDO) at (a) 24h and (b) 36h of co-culture. Alexa Fluor 488-Ac-LDL (green)-labelled endothelial cells were co-cultured with Cy3-labelled miRNA-transfected MDA-MB-231. Co-cultures were counterstained with phalloidin (purple) and DAPI+WGA (blue). A 3D visualization shows the localization of miRNA within the nanoscale connections (white arrows), which act as conduits for horizontal transfer of miRNAs to endothelial cells. (c) Schema shows quantification of Cy3-labelled control miRNA and Cy3-labelled miR132 transfer between cancer cell and endothelium using flow cytometry. Endothelial cell populations were isolated from the co-cultures and percentage of miRNA+ve cells was determined. Dual cultures in Boyden chambers were included as controls. (d) Graph shows the effect of pharmacological disruption of nanoscale conduits on miRNA transfer. (e) Schema shows experimental design for reverse transcriptase–PCR-based detection of transferred miR-132 in endothelial cells under different experimental conditions. MDA-MB-231 cells transfected with miR-132 and α-miR-132 were co-cultured with endothelial tubes. FACS-isolated endothelial cell populations were analysed for the expression of miR-132. (f) Graph shows miR-132+ve cell populations (solid red) show 5 × increase compared with miR-132−ve populations (solid blue) (P<0.0001), whereas anti-miR-132+ve cells (striped red) show 26 × decrease in miR-132 expression (P<0.0001) compared with α-miR-132−ve cells (striped blue). Direct transfection of miR-132 (black) and α-miR-132 (light blue) in endothelial cells is used as positive and negative controls, respectively. Upregulation of miR-132 from baseline was observed in dual culture (solid green), which could be inhibited with anti-miR-132 (striped green). MiR-132 levels are increased compared with dual only in those cells that are positive for intercellular transfer. Fold change was determined compared with endothelial cell transfection with control miRNA (grey). (g) FACS analysis shows nanoscale bridges-mediated transfer of miRNAs leads to changes in p120RasGAP and pAkt (S473) expression downstream of the miR-132 pathway in endothelial cell populations isolated from co-cultures. (h) Graphs show p120RasGAP expression is decreased in the miR-132+ve cell populations and increased in the α-miR-132+ve cell populations, while further downstream miR-132 positively regulates pAkt expression. Data shown are mean±s.e.m. (N=2–5 independent studies, with 3 replicates per study,*P<0.05, **P<0.01, ***P<0.001, ****P<0.0001, analysis of variance followed by Bonferroni’s post-hoctest).

Nanobridge-mediated transfer alters endogenous miRNA profile

Figure 6: Cancer cell–endothelial intercellular transfer alters the endogenous miRNA profile and phenotype of recipient endothelial cells.

 

The complexity of regulatory tumour parenchyma–endothelial communication is increasingly being unravelled7, 50. The altered phenotypic behaviour of the metastatic cancer cells in the presence of endothelial cells observed in this study, instead of forming classical mammospheres, is consistent with the emerging paradigm of modulatory tumour parenchyma–stroma communication and the creation of a pre-metastatic niche. Indeed, a recent study proposed the concept of the formation of a pre-metastatic niche mediated via metastatic cell-secreted exosomes, leading to vascular leakiness at the pre-metastatic sites13. Here we demonstrate that cancer cells form nanoscale membrane bridges, which can act as conduits for horizontal transfer of miRNA from the cancer cells to the endothelium, switching the latter to a pathological phenotype. Our findings reveal that the ability to form the nanoscale conduits with endothelial cells correlates with the metastatic potential of the cancer cell, and that the pharmacological perturbation of these nanoscale connections can lead to a reduction in the metastatic burden in experimental metastasis models. Together, our studies shed new insights into the tumour parenchyma–endothelial communication, adding depth to the emerging paradigm of the ability of a cancer cell to ‘hijack’ a physiological stromal cell for self-gain13.

Indeed, exosomes have emerged as an extensively studied mechanism of horizontal intercellular transfer of information51. However, a key distinction exists between the exosome-mediated versus the nanoscale membrane bridge-mediated intercellular communication. Although the former is stochastic, that is, it is unlikely the cancer cell has control over which cell will be targeted by a secreted exosome, the communication via nanoscale membrane bridges is deterministic, that is, the cancer cell can connect to a specific endothelial cell, which could be further away than the most proximal endothelial cell.

Although the aim of this study was to study the nanoscale membrane bridges as a mode of horizontal transfer of miRNAs from the metastatic cancer cells to the endothelium, and not to characterize a specific miRNA that are implicated in metastasis, many of the miRNAs, which were differentially regulated in the recipient endothelial cells, have previously been shown to regulate metastasis (Supplementary Discussion).

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Tumor Shrinking Triple Helices

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

Tumor-Shrinking Triple-Helices

A braided structure and some adhesive hydrogel make therapeutic microRNAs both stable and sticky.

By Ruth Williams | April 1, 2016

http://www.the-scientist.com/?articles.view/articleNo/45576/title/Tumor-Shrinking-Triple-Helices

 

MicroRNAs (miRs) are small, noncoding ribonucleic acids that control the translation of target messenger RNAs (mRNAs). Given their roles in development, differentiation, and other cellular processes, misregulation of miRs can contribute to diseases such as cancer. Indeed, “they are recognized as important modulators of cancer progression,” says Natalie Artzi of Harvard Medical School.

In addition to occasionally promoting cancer pathology, miRs also hold the potential to treat it—either by restoring levels of suppressed miRs, or by repressing overactive ones using antisense miRs (antagomiRs). While miRs are promising therapeutic molecules, says Daniel Siegwart of the University of Texas Southwestern Medical Center in Dallas, their use “is currently hindered by at least two issues: nucleic acid instability in vivo, and the development of effective delivery systems to transport miRs into tumor cells.”

Artzi and her team have now addressed both of these issues in one fell swoop. They first assembled two therapeutic miRs—one antagomiR and one that replaced a deficient miR—together with a third miR, a complement of the replacement strand, into triple-helix structures, which increased molecular stability without affecting function. They then complexed these helices with dendrimers—large synthetic branching polymer particles—and mixed these complexes with dextran aldehyde to form an adhesive hydrogel. The gel could then be applied directly to the surface of tumors to deliver the therapeutic miRs into cells with high efficiency.

In mice with induced breast tumors, the triple-helix–hydrogel approach led to dramatic tumor shrinkage and extended life span: the animals survived approximately one month longer than those treated with standard-of-care chemotherapy drugs. Because the RNA-hydrogel mixture must be applied directly to the tumor, the approach will not be suitable for all cancers. But one potential application, says Siegwart, is that “the hydrogel could be applied by a surgeon after performing bulk tumor removal…[and] might kill remaining tumor cells that would otherwise cause tumor recurrence.” (Nature Materials, http://dx.doi.org:/10.1038/NMAT4497, 2015)

STICKING IT TO TUMORS: To deliver therapeutic microRNAs (miRs) to tumors, braids of three microRNAs (miRs)—an antisense strand that blocks a miR overactive in cancer, a strand that replaces a deficient miR, and a stabilizing strand (1)—are added to a dendrimer (2) and mixed with a hydrogel scaffold (3). When researchers introduced the sticky gel onto mouse mammary tumors (4), the malignancies shrank and the animals lived longer (5)© GEORGE RETSECK; J.CONDE ET AL., NATURE MATERIALS

 

miR DELIVERY SYSTEM VEHICLE DOSE TUMOR TARGETING APPLICABLE TUMOR TYPES
Nanoparticles Examples: gold particles, liposomes, peptide nucleic acids, or polymers Usually multiple injections Combining miRs with aptamers or antibodies can guide nanoparticles to target cells, but systemic delivery inevitably leads to some off-target dispersion. Multisite or blood cancers
RNA–triple-helix-hydrogel Dendrimer-dextran hydrogel One Adhesive hydrogel sticks miRs to tumor site with minimal dispersion to other tissues. Solid Tumors

 

Self-assembled RNA-triple-helix hydrogel scaffold for microRNA modulation in the tumour microenvironment

João CondeNuria OlivaMariana AtilanoHyun Seok Song & Natalie Artzi
Nature Materials15,353–363(2016)
                         http://dx.doi.org:/10.1038/nmat4497

The therapeutic potential of miRNA (miR) in cancer is limited by the lack of efficient delivery vehicles. Here, we show that a self-assembled dual-colour RNA-triple-helix structure comprising two miRNAs—a miR mimic (tumour suppressor miRNA) and an antagomiR (oncomiR inhibitor)—provides outstanding capability to synergistically abrogate tumours. Conjugation of RNA triple helices to dendrimers allows the formation of stable triplex nanoparticles, which form an RNA-triple-helix adhesive scaffold upon interaction with dextran aldehyde, the latter able to chemically interact and adhere to natural tissue amines in the tumour. We also show that the self-assembled RNA-triple-helix conjugates remain functional in vitro and in vivo, and that they lead to nearly 90% levels of tumour shrinkage two weeks post-gel implantation in a triple-negative breast cancer mouse model. Our findings suggest that the RNA-triple-helix hydrogels can be used as an efficient anticancer platform to locally modulate the expression of endogenous miRs in cancer.

 

Figure 1: Self-assembled RNA-triple-helix hydrogel nanoconjugates and scaffold for microRNA delivery.

Self-assembled RNA-triple-helix hydrogel nanoconjugates and scaffold for microRNA delivery.

a, Schematic showing the self-assembly process of three RNA strands to form a dual-colour RNA triple helix. The RNA triplex nanoparticles consist of stable two-pair FRET donor/quencher RNA oligonucleotides used for in vivo miRNA inhibit…

 

Figure 4: Proliferation, migration and survival of cancer cells as a function of RNA-triple-helix nanoparticles treatment.close

Proliferation, migration and survival of cancer cells as a function of RNA-triple-helix nanoparticles treatment.

a, miR-205 and miR-221 expression in breast cancer cells at 24, 48 and 72h of incubation (n = 3, statistical analysis performed with a two-tailed Students t-test, , P < 0.01). miRNA levels were normalized to the RNU6B reference gene

 

  1. Kasinski, A. L. & Slack, F. J. MicroRNAs en route to the clinic: Progress in validating and targeting microRNAs for cancer therapy. Nature Rev. Cancer 11, 849864 (2011).
  2. Li, Z. & Rana, T. M. Therapeutic targeting of microRNAs: Current status and future challenges. Nature Rev. Drug Discov. 13, 622638 (2014).
  3. Yin, H. et al. Non-viral vectors for gene-based therapy. Nature Rev. Genet. 15, 541555(2014).
  4. Conde, J., Edelman, E. R. & Artzi, N. Target-responsive DNA/RNA nanomaterials for microRNA sensing and inhibition: The jack-of-all-trades in cancer nanotheranostics? Adv. Drug Deliv. Rev. 81, 169183 (2015).
  5. Chen, Y. C., Gao, D. Y. & Huang, L. In vivo delivery of miRNAs for cancer therapy: Challenges and strategies. Adv. Drug Deliv. Rev. 81, 128141 (2015).
  6. Yin, P. T., Shah, B. P. & Lee, K. B. Combined magnetic nanoparticle-based microRNA and hyperthermia therapy to enhance apoptosis in brain cancer cells. Small 10, 41064112(2014).
  7. Hao, L. L., Patel, P. C., Alhasan, A. H., Giljohann, D. A. & Mirkin, C. A. Nucleic acid–gold nanoparticle conjugates as mimics of microRNA. Small 7, 31583162 (2011).
  8. Endo-Takahashi, Y. et al. Systemic delivery of miR-126 by miRNA-loaded bubble liposomes for the treatment of hindlimb ischemia. Sci. Rep. 4, 3883 (2014).
  9. Chen, Y. C., Zhu, X. D., Zhang, X. J., Liu, B. & Huang, L. Nanoparticles modified with tumor-targeting scFv deliver siRNA and miRNA for cancer therapy. Mol. Ther. 18, 16501656(2010).
  10. Anand, S. et al. MicroRNA-132-mediated loss of p120RasGAP activates the endothelium to facilitate pathological angiogenesis. Nature Med. 16, 909914 (2010).

 

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Cambridge Healthtech Institute’s Third Annual

Clinical NGS Assays

Addressing Validation, Standards, and Clinical Relevance for Improved Outcomes

August 23-24, 2016 | Grand Hyatt Hotel | Washington, DC


View Preliminary Agenda

Molecular diagnostics, particularly next-generation sequencing (NGS), have become an integral component of disease diagnosis. Still, there is work to be done to establish these tools as the standard of care. The Third Annual Clinical NGS Assays event will address NGS assay validation, establishing NGS standards, and determining clinical relevance. The pros and cons of various techniques such as gene panels, whole exome, and whole genome sequencing will also be debated with regards to depth of coverage, clinical utility, and reimbursement. Overall, this event will address the needs of both researchers and clinicians while exploring strategies to increase collaboration for improved patient outcomes.

Special Early Registration Savings Available
Register Now to Save up to $450

Preliminary Agenda

ASSAY VALIDATION AND ANALYSIS

Best Practices for Using Genome in a Bottle Reference Materials to Benchmark Variant Calls
Justin Zook, National Institute of Standards and Technology

NGS in Clinical Diagnosis: Aspects of Quality Management
Pinar Bayrak-Toydemir, M.D., Ph.D., FACMG, Associate Professor, Pathology, University of Utah; Medical Director, Molecular Genetics and Genomics, ARUP Laboratories

Thorough Validation and Implementation of Preimplantation Genetic Screening for Aneuploidy by NGS
Rebekah Zimmerman, Ph.D., Laboratory Director, Clinical Genetics, Foundation for Embryonic Competence

EXOME INTERPRETATION CHALLENGES

Are We There Yet? The Odyssey of Exome Analysis and Interpretation
Avni B. Santani, Ph.D., Director, Genomic Diagnostics, Pathology and Lab Medicine, The Children’s Hospital of Philadelphia

Challenges in Exome Interpretation: Intronic Variants
Rong Mao, M.D., Associate Professor, Pathology, University of Utah; Medical Director, Molecular Genetics and Genomics, ARUP Laboratories

Exome Sequencing: Case Studies of Diagnostic and Ethical Challenges
Lora J. H. Bean, Ph.D., Assistant Professor, Human Genetics, Emory University

ESTABLISHING STANDARDS

Implementing Analytical and Process Standards
Karl V. Voelkerding, M.D., Professor, Pathology, University of Utah; Medical Director for Genomics and Bioinformatics, ARUP Laboratories

Assuring the Quality of Next-Generation Sequencing in Clinical Laboratory Practice
Shashikant Kulkarni, M.S., Ph.D., Professor, Pathology and Immunology; Head of Clinical Genomics, Genomics and Pathology Services; Director, Cytogenomics and Molecular Pathology, Washington University at St. Louis

Sponsored Presentation to be Announced by Genection

PANEL DISCUSSION: GENE PANEL VS. WHOLE EXOME VS. WHOLE GENOME

Panelists:
John Chiang, Ph.D., Director, Casey Eye Institute, Oregon Health & Science University
Avni B. Santani, Ph.D., Director, Genomic Diagnostics, Pathology and Lab Medicine, The Children’s Hospital of Philadelphia
Additional Panelist to be Announced

DETERMINING CLINICAL SIGNIFICANCE AND RETURNING RESULTS

Utility of Implementing Clinical NGS Assays as Standard-of-Care in Oncology
Helen Fernandes, Ph.D., Pathology & Laboratory Medicine, Weill Cornell Medical College

An NGS Inter-Laboratory Study to Assess Performance and QC – Sponsored by Seracare
Andrea Ferreira-Gonzalez, Ph.D., Chair, Molecular Diagnostics Division, Pathology, Virginia Commonwealth University Medical School

This conference is part of the Eighth Annual Next-Generation Dx Summit.


Track Sponsor: SeraCare


For exhibit & sponsorship opportunities, please contact:

Joseph Vacca, M.Sc.
Associate Director, Business Development
Cambridge Healthtech Institute
T: (+1) 781-972-5431
E: jvacca@healthtech.com

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