ONCOLOGY: How some immune cells improve cancer outcome

For a number of cancers, including neuroblastoma (the second most common tumor in children), tumor infiltration by a subset of immune cells known as V-alpha-24-invariant NKT cells is associated with a favorable outcome. But how these cells have an anticancer effect is unclear, as many tumors do not express the protein that V-alpha-24-invariant NKT cells target. However, Leonid Metelitsa and colleagues, at the University of Southern California Keck School of Medicine, and The Saban Research Institute of Childrens Hospital Los Angeles, Los Angeles, have now shown, in vitro and in mice, that human V-alpha-24-invariant NKT cells indirectly affect neuroblastoma growth by killing tumor-associated cells that promote the growth of neuroblastoma cells.

In the study, human tumor-associated cells known as monocytes/macrophages were found to produce the soluble factor IL-6, which further analysis revealed stimulates the growth of neuroblastoma cells in vitro and after they have been transplanted into mice. As expected, human V-alpha-24-invariant NKT cells did not kill neuroblastoma cells in vitro, but they did kill monocytes pulsed with tumor antigens. Consistent with this, the growth of neuroblastoma cells was substantially impaired in mice infused with monocytes and V-alpha-24-invariant NKT cells, when compared to mice only receiving monocytes. These data therefore provide insight into a mechanism by which V-alpha-24-invariant NKT cells can impact cancer outcome.

TITLE: V-alpha-24-invariant NKT cells mediate antitumor activity via killing of tumor-associated macrophages in mice and humans

AUTHOR CONTACT:
Leonid S. Metelitsa
Baylor College of Medicine, Houston, Texas, USA.

View the PDF of this article at: https://www.the-jci.org/article.php?id=37869

METABOLISM: The sweet smell of success: new understanding of the pathway affected in Maple Syrup Urine Disease

Yibin Wang and colleagues, at UCLA David Geffen School of Medicine, Los Angeles, have identified, in cultured cells and mice, a protein responsible for regulating the protein complex that breaks down branched-chain amino acids (three protein building blocks that cannot be made by humans but have to be obtained from the food we eat). Mice lacking this protein (PP2Cm) exhibited similar symptoms to some forms of human Maple Syrup Urine Disease (MSUD), an inherited disorder characterized by sweet-smelling urine that leads to severe brain damage and death if untreated. The authors therefore suggest that defects in PP2Cm may be responsible for some cases of MSUD.

TITLE: Protein phosphatase 2Cm is a critical regulator of branched chain-amino acid catabolism in mice and cultured cells

AUTHOR CONTACT:
Yibin Wang
David Geffen School of Medicine, University of California, at Los Angeles, Los Angeles, California, USA.

View the PDF of this article at: https://www.the-jci.org/article.php?id=38151

CARDIOLOGY: The fog lifts on the role for the protein Fog2 in the adult heart

The protein Fog2, which is a regulator of gene expression, is essential for embryonic development of both the heart and the blood vessels that supply the heart (coronary blood vessels), but its role in the adult heart has not been determined. However, William Pu and colleagues, at Children’s Hospital Boston, have now determined that Fog2 regulates adult mouse heart function and the growth of new coronary vessels.

The authors generated mice lacking Fog2 in heart muscle cells either early or late in embryonic heart development. As has been observed for mice lacking Fog2 in all cells from the point of conception, mice in which Fog2 was deleted early in heart development died before birth, with the same heart and coronary vessel defects. By contrast, mice in which Fog2 was deleted later in heart development survived until 8???? weeks after birth. However, these mice had decreased heart function and insufficient coronary vessels, which led to a lack of oxygen passing to the heart muscle cells and thereby death of the cells and scarring of the heart muscle. These data indicate that Fog2 is required for maintaining heart and coronary vessel function in the adult mouse heart.

TITLE: Fog2 is critical for cardiac function and maintenance of coronary vasculature in the adult mouse heart

AUTHOR CONTACT:
William T. Pu
Children’s Hospital Boston, Boston, Massachusetts, USA.

View the PDF of this article at: https://www.the-jci.org/article.php?id=38723

AUTOIMMUNITY: Two opposing roles for the protein Bim: control of T cell activation and death

The protein Bim has previously been shown to have a role in the cellular process that kills developing T cells (a subset of immune cells) that are ‘born’ with the ability to attack the body’s own tissues and cause autoimmune diseases. Surprisingly, Youhai Chen and colleagues, at University of Pennsylvania School of Medicine, Philadelphia, have now found that Bim also has a role in controlling the activation of mouse T cells.

In the study, in mouse models of two autoimmune diseases, multiple sclerosis and type 1 diabetes, mice with T cells that lacked Bim were observed to be protected from disease. In vitro analysis indicated that following stimulation, T cells lacking Bim were impaired in their ability to produce soluble factors known as cytokines (molecules that execute T cell effects). At the molecular level, Bim was shown to control T cell activation via an IP3R/calcium/NFAT pathway. As the authors point out, this study reveals that Bim joins a growing list of proteins with dual roles in T cell activation and death.

TITLE: Critical roles of Bim in T cell activation and T cell-mediated autoimmune inflammation in mice

AUTHOR CONTACT:
Youhai H. Chen
University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.

View the PDF of this article at: https://www.the-jci.org/article.php?id=37619

Source:
Karen Honey

Journal of Clinical Investigation

Identifying one of the processes that plays a role in naïve and memory T-cells’ growth and production could one day lead to better vaccines and possibly more effective cancer immunotherapy, said researchers at Baylor College of Medicine and Texas Children’s Hospital in a report that appears in the current edition of Nature Immunology.

In previous work, Dr. Daniel Lacorazza, assistant professor of pathology at BCM, along with his research team, identified a transcription factor, ELF4, which regulates blood stem cells. A transcription factor is a protein that regulates how genes are translated into a form that leads to the making of the proteins associated with them.

“We knew ELF4 played a role in maintaining T cells,” said Lacorazza, who is the principal investigator of the current study. “What we discovered was that ELF4 activates an inhibitor that leads to cell arrest, stopping naive T cells from proliferation.”

A population of naïve CD8 T-cell is always circulating in the body and maintained at a constant level. Memory T cells are created when naïve CD8 T cells are activated to fight intracellular pathogens such as viruses or bacteria. The fight against infections prompts creation of memory T cells that then “remember” antigens or proteins found on cells infected with viruses or bacteria. In the future when same infections arise, memory T-cell enhances the body’s ability to fight them.

Lacorazza and his research team focused on how ELF4 affected the process of inhibiting proliferation of CD8 T cells. Using mice generated to lack ELF4, researchers found that CD8 T-cells grew over time and acquired a “memory phenotype” without being exposed to any type of infections. At the same time, they determined that expression of the tumor suppressor gene called KLF4 was reduced in these mice.

“We discovered that ELF4 directly activates the tumor suppressor KLF4, which signals cell cycle arrest in naïve CD8 T cells,” Lacorazza said. “This inhibitory process is important to T cells because it stops them from proliferating out of control.” Cell cycle arrest means the cells do not go through the normal events of their life cycles: growth, replication and division. The description of cell intrinsic regulation of quiescence in normal T cells will provide insights on the pathobiology of lymphoid malignancies.

The researchers then immunized mice deficient for ELF4 to test their immune response. These mice had a larger memory T cell response, indicating that the absence of ELF4 eliminated control over the proliferation of CD8 T cells.

“If we can control ELF4 activation during vaccination, we can enhance long-term immune response, making a vaccine more effective,” Lacorazza said.

“We could enhance in vitro T cell activation of T cells extracted from patients to heighten immune response”, said Lacorazza. “In addition, a future line of study is to determine whether deletion of KLF4 expands pre-leukemic clones leading to overt leukemia in pediatric patients”.

Lacorazza said these are still hypotheses, but understanding the process that controls T cell proliferation will help in future research.

Other researchers who were a part of the study include Takeshi Yamada and Chun Shik Park, both postdoctoral associates in the Pathology Department at BCM, and Maksim Mamonkin, graduate student in the Department of Immunology at BCM.

Funding for the research was provided by the National Institutes of Health, the Curtis Hankamer Basic Research Fund (Junion-Faculty Seed Award) and a pilot project of the Dan Duncan Cancer Center at BCM.

Source:
Graciela Gutierrez

Baylor College of Medicine

The following highlights efforts that seek to reduce racial and ethnic health disparities.

• American Society of Clinical Oncology: ASCO on Wednesday released a policy statement that makes recommendations for eliminating cancer disparities. The statement, which was published in the Journal of Clinical Oncology, recommends increasing research, boosting enrollment of minorities in cancer clinical trials, encouraging greater diversity in the oncology workforce, educating the oncology workforce about cultural issues and disparities and ensuring equal access to quality health care. ASCO also announced the 2009 recipients of its Diversity in Oncology Initiative awards, a program in partnership with Susan G. Komen for the Cure that aims to reduce health care disparities by boosting the number of minority oncologists (ASCO release, 4/29).
  
  
• Detroit: Gospel music artist Yolanda Adams, through a partnership with AARP and Radio One, recently stopped in Detroit for a Health & Wellness tour, which aims to encourage healthy living in the black community, the Detroit News reports. The event included no-cost health screenings and seminars. Adams also targets the black religious community with health messages through her nationally syndicated radio show (Hayes Taylor, Detroit News, 4/24).
  
  
• National Minority Quality Forum: NMQF has announced that it is launching a database that tracks cardiovascular disease nationwide, called CVD Atlas. CVD Atlas, which is a component of an existing database by NMQF, enables users to map the prevalence of CVD by state, legislative district, age, gender, race and ethnicity. The American College of Cardiology and Novartis Pharmaceuticals Corporation both support the system (NMQF release, 4/27).
  

Reprinted with kind permission from http://www.kaisernetwork.org. You can view the entire Kaiser Daily Health Policy Report, search the archives, or sign up for email delivery at http://www.kaisernetwork.org/dailyreports/healthpolicy. The Kaiser Daily Health Policy Report is published for kaisernetwork.org, a free service of The Henry J. Kaiser Family Foundation.

© 2009 Advisory Board Company and Kaiser Family Foundation. All rights reserved.

Now, for the first time, experts have compiled a comprehensive overview of the literature regarding the usefulness of PET imaging for the treatment of several cancers. Personalizing Cancer Therapy with FDG PET: From RECIST to PERCIST - a compilation of results of therapeutic regimens across a broad range of cancers published as a supplement to The Journal of Nuclear Medicine is a unique reference tool presenting the most up-to-date information about the use of fluorodeoxyglucose and positron emission tomography (FDG PET) for monitoring therapy and treatment of many different cancers. Internationally recognized PET imaging specialists and oncologists contributed to and developed this new supplement.

FDG PET is a noninvasive, painless molecular imaging technology that allows physicians to determine how organs and tissues inside the body are functioning on a molecular and cellular level. In the past, collecting information about tumor response in a structured and meaningful format was difficult. As a result, generally accepted criteria for response assessment in solid tumors did not exist. Because each patient is unique, oncologists have no way of accurately predicting which patient will benefit from a specific therapy.

Those involved in the production of the new supplement believe that the international guidelines and criteria for response assessment using PET in solid tumors provided by the new periodical may notably alter cancer treatment and prognosis.

“The literature in this publication suggests that FDG PET could play a significant role in personalizing the treatment of malignant tumors,” said Wolfgang Weber, M.D., editor of the supplement and medical director with the division of nuclear medicine at the Albert-Ludwigs University in Freiburg, Germany. “It could positively impact patient care by providing access to critical imaging procedures to ensure that patients get the right treatment early on in their cancer.”

Most anticancer drugs are effective only in subgroups of patients, and many of the various techniques developed to monitor tumor response to these drugs have proven to be inadequate. “FDG PET imaging, on the other hand, has been shown to improve response assessment in several tumor types, such as lymphoma, and a variety of single-center studies have shown that FDG PET may provide earlier or more accurate assessment of tumor response in other types of cancer.

Because the supplement aims to present a careful discussion of the available literature and provide guidance for treatment monitoring with FDG PET, researchers involved in a wide range of cancer studies were given templates to use for reporting purposes to ensure that data was collected in a meaningful way. The researchers then methodically summarized strengths and weaknesses of various approaches for predicting or monitoring tumor response, and described common methodological differences between individual studies and their effects on the reported diagnostic accuracy of FDG PET.

“Previously, researchers used different criteria and their results were inconsistent,” explained Weber. “The tabulated format we required for this publication provided the necessary structure to gather data and made it possible to compare results from different studies, making it easier for doctors to find valuable information in a uniformly structured and centralized location.”

Source:
Amy Shaw

Society of Nuclear Medicine

Cougar Biotechnology, Inc. (NASDAQ: CGRB) announced the initiation of a Phase III clinical trial (COU-AA-302) of its lead drug candidate CB7630 (abiraterone acetate) in patients with chemotherapy-naïve castration-resistant prostate cancer (CRPC). The COU-AA-302 Phase III trial is a randomized, double-blind, placebo-controlled trial of CB7630 plus prednisone in patients with metastatic CRPC who have not yet received treatment with chemotherapy. The trial is expected to enroll approximately 1,000 patients who will be randomized (1:1) to receive either CB7630 plus prednisone or placebo plus prednisone. The trial will be conducted at approximately 150 sites in North America, Europe and Australia. The co-primary endpoints of the trial are progression free survival and overall survival. The Company plans to use the progression free survival data from the trial as the basis for submission of a New Drug Application and a Marketing Authorization Application for Accelerated and Conditional Approval from the regulatory agencies.

Alan H. Auerbach, Chief Executive Officer and President of Cougar Biotechnology, said, “Initiation of this Phase III trial of CB7630 in chemotherapy-naïve prostate cancer patients represents an important milestone in the clinical development of CB7630. As these patients continue to represent a market that is underserved with current treatments, we are pleased to initiate the COU-AA-302 Phase III trial in this patient population.”

Arturo Molina, M.D., M.S., FACP, Chief Medical Officer and Executive Vice President of Clinical Research and Development of Cougar, added, “The interim results of our Phase II trials of CB7630 have shown strong evidence of antitumor activity in patients with metastatic CRPC who have not yet received chemotherapy; therefore, we are pleased to initiate the COU-AA-302 Phase III trial in this patient population. Due to the high level of awareness of CB7630 in the urology and medical oncology communities, we look forward to aggressively enrolling this Phase III trial.”

Source
Cougar Biotechnology

CHICAGO, April 29 — Going against the flow on PSA testing, which has been questioned as a general prostate cancer screen elsewhere, the American Urological Association now recommends that physicians start offering the test to men at age 40.

The rationale for an earlier baseline test is that a PSA value above the median at a relatively young age portends an increased risk of prostate cancer, said Peter Carroll, M.D., who chaired the AUA panel that developed the recommendation.

After a baseline measurement, subsequent PSA testing should be individualized to a man’s risk profile.

“The single most important message of this statement is that prostate cancer testing is an individual decision that patients of any age should make in conjunction with their physicians and urologists,” said Dr. Carroll, of the University of California San Francisco. “There is no single standard that applies to all men, nor should there be at this time. ”