Hirshberg Foundation Awards and Grants 2010

We are pleased to announce the selection of 2010-2011 Hirshberg Foundation for Pancreatic Cancer Research Seed Grant Award recipients. The purpose of our seed grant program is to impact the understanding of pancreatic cancer cell biology, biochemistry, physiology and response to treatment. We hope that future collaborations among researchers from major cancer institutions will advance our goal of improved treatment options and the eventual cure for this disease.

	Andrea Viale, MD Dana Farber Cancer Institute, Boston, MA Department of Medical Oncology “The role of oncogenic K-RAS in self–renewal and maintenance of cancer stem cells in pancreatic cancer”

	Ying Ma, PhD University of Texas, MD Anderson Cancer Center, Houston, TX Department of Immunology “Mast cell blockage as immunotherapy for pancreatic cancer”

	Larry Karnitz, PhD Mayo Clinic, Rochester, MN Department of Radiation Oncology “An innovative drug combination for pancreatic cancer”

	Guido Eibl, MD University of California, Los Angeles, CA Department of Surgery “Western diet-induced pancreatic cancer”

The Hirshberg Foundation awards the best abstract presentations during the national meeting of the American Pancreatic Association (APA), which brings together an international group of scientists and clinicians to identify the best course of treatment and discuss the most up to date research results for pancreatic diseases. The 41st Annual APA Meeting was held November 3-6, 2010 in Chicago. The Hirshberg Foundation sponsored the keynote lecture, as well as the awards for Best Clinical Abstract and Best Basic Science Abstracts.

We are pleased to announce the 2010 APA Award Recipients.

Best Clinical Abstract
Presented to: Gaurav Aggarwal, MBBS
Mayo Clinic
New onset Diabetes in Pancreatic Cancer: A study in the primary care setting

Best Basic Science Abstract
Presented to: Farzad Esni, PhD
University of Pittsburgh
Loss of Hif2a Accelerates the Progression of Kras-Mediated Pancreatic Neoplasia

UCLA Surgeons Identify Molecular Pathway That May Help Target Future Therapies Against Tumor Angiogenesis

UCLA SURGEONS IDENTIFY MOLECULAR PATHWAY THAT MAY HELP
TARGET FUTURE THERAPIES AGAINST TUMOR ANGIOGENESIS
Study provides a new look at molecular contributors to angiogenesis

CHICAGO—Researchers at the University of California Los Angeles (UCLA) have found that a second molecular pathway may need to be blocked to prevent malignant cells from creating new blood vessels [angiogenesis]. A study of patients with pancreatic cancer showed that CXCL5 may be a key molecule in the angiogenesis switch—the point at which cells stop being normal and start producing blood vessels that feed malignancy. Findings from the study were presented at the 2009 Clinical Congress of the American College of Surgeons. CXCL5 is one member of a family of molecules that may play a role in the development of future anti-angiogenesis treatments. “CXC peptides have been shown to cause cancer cells to multiply and migrate and tumors to form new blood vessels. With data from this study as well as other studies, we’re showing that we need to pay attention to the CXCL5 molecule because there appears to be multiple pathways driving tumor angiogenesis,” according toJonathan C. King, MD, a surgical resident at UCLA.

The study showed that patients who had high levels of CXCL5 were more likely to have cancer at a more advanced stage, more poorly differentiated and therefore more aggressive tumors, and greater density of small tumor blood vessels than those who had low levels of the molecule. The patients also were far more likely to die quickly from the disease. Patients whose tumors had low levels of expression of CXCL5 lived 25.5 months longer than those whose tumors had high levels of expression of the molecule. “Patients who express a lot of CXCL5 in their tumors have significantly decreased survival overall, and part of the reason may be that the tumors are better able to promote angiogenesis than the high-CXCL5-producing tumors,”
Dr. King said.

In addition, the researchers found that lesions considered to be immediate precursors of pancreatic cancer [pancreatic intraepithelial neoplasia or PanIN] were more likely to express higher levels of CXCL5 using laboratory staining techniques. “PanIN were found to stain more intensely along the spectrum from dysplasia [abnormal cellular growth] to malignancy [uncontrolled new growth]. So a low-grade PanIN lesion had little to no CXCL5 expression, while the high-grade lesions had relatively high expression of the molecule,” Dr. King explained. This finding provides further support for the theory that CXCL5 may be involved in the angio- genic switch. “When CXCL5 is expressed may be an important stage in the development of cancer,” he added.
Although the study examined clinical data and surgical specimens from 153 patients with pancreatic cancer, the action of the CXCL5 molecule is not specific to this form of malignancy.

“CXCL5 is a molecule that is released from all kinds of solid tumors that require new blood vessel formation to grow. The application [of CXCL5 as a target of angiogenesis therapy] is potentially far broader than for just pancreatic cancer,” Dr. King said. Results from the study are leading researchers to take a whole new look at angiogenesis and its molecular contributors. Vascular endothelial growth factor (VEGF) has been the principal focus of angiogenesis research because of its strong links to the process of generating new blood vessels by malignant cells. Treatments directed against the action of VEGF have not favorably influenced the survival of patients with pancreatic cancer, however. UCLA and other researchers therefore have been exploring whether other molecules besides VEGF are enabling tumors to grow new blood vessels. “Drs. Li and Hines have focused on CXCL5, but there are other CXC molecules—CXCL8 and CXCL1—that are pro-angiogenic. If we can target these molecules along with VEGF, the thought is that treatment against angiogenesis would be more powerful than targeting one of the molecules alone,” he added. Aihua Li, PhD, and principal investigator O. Joe Hines, MD, FACS, have been working together to elucidate the roles of CXC molecules for years and contributed to the conception, design, and technical oversight of the study. In addition to Drs. Li and Hines, Mark D. Sugi, BS; David Dawson, MD, FACS; Guido Eibl, MD; and Howard A. Reber, MD, participated in this study.

Metformin reduces the growth of pancreatic cancer

Metformin (Glucophag) reduces the growth of pancreatic cancer

Investigators supported by the Hirshberg Foundation, including dr Kisfalvi (a recipient of a seed grant from the Foundation), Dr. Eibl (Hirshberg Laboratories at UCLA) and Dr. Rozengurt (the Hirshberg Chair in Pancreatic Cancer Research) have shown that metformin, the most widely prescribed drug for the treatment of type 2 diabetes mellitus, inhibit pancreatic cancer growth in preclinical animal models and human pancreatic cancer cells in culture. As the current therapies for pancreatic cancer offer very limited survival benefits, novel therapeutic strategies are urgently required to prevent and treat this aggressive disease. The recent studies of the team headed by Dr. Rozengurt have just appeared in the prestigious journal Cancer Research (see reference, below), as the first publication on the mechanism of metformin in human pancreatic cancer.

The new results assume an added importance in view of the fact that metformin is an FDA-approved drug (Glucophag) currently used in the treatment of type 2 diabetes mellitus. Additional interest in the new research is provided by recent epidemiological studies indicating that administration of metformin reduces the incidence and improves prognosis in pancreatic cancer patients. For example, a recent epidemiological report linked administration of metformin with a 62% reduced risk of pancreatic cancer in patients with type-2 diabetes mellitus (Li D, Yeung SC, Hassan MM, Konopleva M, Abbruzzese Gastroenterology. 2009; 137: 482-8.). Epidemiological studies from other groups from the UK also confirmed that metformin therapy (but not other antidiabetic drugs in use) is associated with greatly reduced risk of pancreatic cancer. However, epidemiological studies can not define the precise mechanism(s) by which metformininhibits the proliferation of cancer cells. Indeed, it was not known whether metformin has any direct effect on pancreatic cancer growth. The recent work of the team headed by Dr. Rozengurt shows that metformin disrupts a crosstalk between insulin receptor and other growth-factor signaling systems in human pancreatic cancer cells. The most interesting piece of new information is that administration of metformin markedlyinhibited the growth of human pancreatic cancer cells in animal models.

Please click here for the full article

The new results in Cancer Research provide a plausible mechanism for the beneficial effect of metfomin seen in diabetic patients and provide a rationale for influencing clinical practice in the management of conditions (including obesity and type 2 diabetes mellitus) that increase pancreatic cancer risk. Specifically, in the light of the new research, metformin should be selected as a first choice in the treatment of type 2 diabetes mellitus (as prevention for developing cancer) and should be considered to be included in the design of novel therapeutic strategies for pancreaticcancer.

Reference: Kisfalvi K, Eibl G, Sinnett-Smith J, Rozengurt E. Metformin disrupts crosstalk between G protein-coupled receptor and insulin receptor signaling systems and inhibits pancreatic cancer growth. Cancer Research 2009; 69: 6539-45.

Risk of Pancreatic Cancer Linked to Variation in Gene that Determines Blood Type

From: http://www.cancer.gov/newscenter/pressreleases/ABOvariantPanScan

Risk of Pancreatic Cancer Linked to Variation in Gene that Determines Blood Type

Common variants of the gene that determines human blood type are associated with an increased risk of pancreatic cancer, according to a study by scientists at the National Cancer Institute (NCI), part of the National Institutes of Health, and colleagues from many universities and research institutions. The study, published online Aug. 2, 2009, in Nature Genetics, is consistent with an observation first made more than 50 years ago.

In the study, the researchers discovered that genetic variation in a region of chromosome 9 that contains the gene for ABO blood type was associated with pancreatic cancer risk. Individuals with the variant that results in blood types A, B, or AB were at an increased risk of pancreatic cancer, compared to those with the variant for blood type O. This finding is consistent with previous research, some of it dating back to the 1950s and 1960s, that had shown increased risks of gastric and pancreatic cancer among individuals of the A and B blood groups (i.e., blood types A, B, and AB). The latest results provide a genetic basis for those earlier observations.

A person’s blood type depends on which form or forms of the ABO gene they inherit from their parents. The protein produced by the ABO gene determines the type of carbohydrates (complex sugars) that are present on the surface of red blood cells and other cells, including cells of the pancreas. The proteins encoded by the A and B forms of the gene transfer different carbohydrates onto the cell surfaces to make A and B blood types. The O form encodes a protein that is unable to transfer carbohydrates. Studies by other researchers have shown that ABO protein encoding in pancreatic tumor cells is different than in normal pancreatic cells.

Genotyping chip with raw data -- red or green indicates identical copies of DNA inherited from both parents and yellow indicates copies from each parent are different.

To discover genetic variations that contribute to pancreatic cancer risk, the research team conducted a genome-wide association study (GWAS). In a GWAS, researchers analyze common variants, called single-nucleotide polymorphisms (SNPs), in the genomes of people with a disease and people without the disease. Initially, the research team studied the genomes of 1,896 patients with pancreatic cancer and 1,939 control subjects to identify SNPs with a strong association with pancreatic cancer. The team then verified its findings by studying the genomes of another 2,457 people with pancreatic cancer and 2,654 people without the disease. In the end, they identified several SNPs on the long arm of chromosome 9 that were associated with pancreatic cancer risk and mapped to the ABO gene.

“Only by working across disciplines and with more than a dozen research groups were we able to make this important discovery of the potential role of the ABO gene in pancreatic cancer risk,” said co-author Patricia Hartge, Sc.D., of NCI’s Division of Cancer Epidemiology and Genetics (DCEG). “Although it will take much more work, this finding may lead to improved diagnostic and therapeutic interventions that are so desperately needed.”

Pancreatic cancer is the fourth leading cause of cancer death in the United States. It is difficult to detect, and in many people it is not diagnosed until after the disease has spread to other parts of the body. Less than five percent of Americans with pancreatic cancer survive five years past diagnosis. Risk factors include smoking, diabetes, race, and a family history of the disease. The risk of getting pancreatic cancer is about twice as high among smokers compared to those who have never smoked. When it comes to giving up smoking, there are a wide variety of different solutions available. For example, an increasing number of people are turning to vaping – using e-cigarettes to inhale vapours produced by e-liquids such as those in the Air Factory range – as a safer alternative. Additional stop smoking aids include nicotine patches and gum.

“Pancreatic cancer is the newest beneficiary of so-called high-throughput genotyping that, over the past two years, has yielded scores of genetic hot-spots linked to risk for cancer and other diseases,” said co-author Stephen J. Chanock, M.D., chief of NCI’s Laboratory of Translational Genomics in DCEG. “As more variants are discovered and follow-up studies are conducted to examine the biological effects of these variants, a better understanding will emerge of the inherited risk factors and mechanisms that lead to the development of pancreatic cancer.”

The study was part of PanScan, a GWAS of pancreatic cancer conducted by the Pancreatic Cancer Cohort Consortium, composed of 14 academic centers. The investigators are conducting whole-genome scans to identify common genetic variants that may be markers of susceptibility to pancreatic cancer.

Analyses and data from PanScan will be available through NCI’s caBIG (Cancer Biomedical Informatics Grid). The summary results for similar data on breast and prostate cancer are already freely available to other researchers at this Web site.

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For more information on Dr. Hartge’s research, please go to http://dceg.cancer.gov/about/staff-bios/hartge-patricia.

For more information on Dr. Chanock’s research, please go to http://dceg.cancer.gov/about/staff-bios/chanock-stephen.

For more information about PanScan, please go to http://epi.grants.cancer.gov/PanScan.

NCI leads the National Cancer Program and the NIH effort to dramatically reduce the burden of cancer and improve the lives of cancer patients and their families, through research into prevention and cancer biology, the development of new interventions, and the training and mentoring of new researchers. For more information about cancer, please visit the NCI Web site at http://www.cancer.gov or call NCI’s Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).

Reference: Amundadottir L., et al. Genome-wide association study identifies ABO Blood Group Susceptibility Variants for Pancreatic Cancer. Nature Genetics. Online August 2, 2009.

UCLA Center for Excellence in Pancreatic Diseases launches new website

UCLA Center for Excellence in Pancreatic Diseases launches new website.

www.pancreaticdiseasecenter.org

Phase One Clinical Trial

The Macrobead Phase One Clinical Trial
1/4/2008

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