The American Association for Cancer Research (AACR) is the oldest and largest scientific organization in the world focused on every facet of cancer research. AACR was founded in 1907 by 11 physicians and scientists interested in research with the goal to “to further the investigation and spread the knowledge of cancer.” Since then, the AACR has grown to 33,000 members and publishes seven peer-reviewed journals: Cancer Research; Clinical Cancer Research; Molecular Cancer Therapeutics; Molecular Cancer Research; Cancer Epidemiology, Biomarkers & Prevention; and Cancer Prevention Research, and launched a new journal in 2010, Cancer Discovery.

AACR’s mission is to accelerates progress toward the prevention and cure of cancer by promoting research, education, communication, and collaboration.

The 102nd Annual Meeting 2011 begins April 2 in Orlando FL and will feature over 6000 abstracts presented by basic science, translational, and clinical researchers. Over 17,000 attendees and presenters will learn in a variety of settings: plenary lectures, symposia, minisymposia, workshops, poster sessions, and other formats.

A selection of neuroblastoma-related presentations

Several presentations and posters on neuroblastoma are of interest. Click on the title to see the abstract on AACR site.

4336/4 – Oncolytic reovirus as a novel therapy for neuroblastoma Amelia Kellar, Nicole Redding, Karen Blote, Qiao Shi, Jason Spurrell, Paul Beaudry, Don Morris. University of Calgary, Calgary, AB, Canada Poster Session

4340/8 – Sorafenib induces growth arrest and apoptosis in neuroblastoma cells via inhibition of JAK2/STAT3 and MEK1/2/MAPK (p44/42) signaling pathways Fan Yang¹, Veronica Jove¹, Ralf Buettner¹, Hong Xin¹, Sangkil Nam¹, Tasnim Ara², Yves A. DeClerck², Robert C. Seeger², Hua Yu¹, Richard Jove¹. ¹City of Hope, Duarte, CA; ²The Saban Research Institute of Children’s Hospital Los Angeles, Los Angeles, CA Poster Session

4346/14 – Differential response of a novel protein kinase C-iota inhibitor (ICA-1) on neuroblastoma cells Prajit P. Pillai, Mildred Acevedo-Duncan. Univ. of South Florida, Tampa, FL Poster Session

954 – ABCC/MRP multidrug transporters contribute to neuroblastoma biology, pathogenesis and clinical outcome, independently of any role in cytotoxic drug efflux Murray D. Norris¹, Michelle J. Henderson¹, Antonio Porro², Marcia Munoz¹, Nunzio Iraci², Chengyuan Xue¹, Jayne Murray¹, Claudia Flemming¹, Jamie Fletcher¹, Samuele Gherardi², Alan Kwek¹, Amanda Russell¹, Wendy B. London³, Allen B. Buxton³, Lesley Ashton¹, Alan C. Sartorelli⁴, Susan L. Cohn⁵, Manfred Schwab⁶, Glenn M. Marshall¹, Giovanni Perini², Michelle Haber¹. ¹Children’s Cancer Institute Australia, Sydney, Australia; ²University of Bologna, Bologna, Italy; ³University of Florida and Children’s Oncology Group Statistics and Data Center, Gainesville, FL; ⁴Yale University School of Medicine, New Haven, CT; ⁵University of Chicago, Chicago, IL; ⁶German Cancer Research Center, Heidelberg, Germany Minisymposium

4758 – Inhibition of checkpoint kinase 1 (Chk1) as a potential therapeutic for pediatric neuroblastoma Mike R. Russell, Kristina A. Cole, John M. Maris. Children’s Hospital of Philadelphia, Philadelphia, PA Minisymposium

LB-312/3 – Methylated RASSF1a is the first specific DNA marker for minimal residual disease testing in neuroblastoma Janine Stutterheim, Fatima Ait Ichou, Emmy Den Ouden, Rogier Versteeg, Huib N. Caron, Godelieve A.M. Tytgat, C. Ellen Van der Schoot. Sanquin, Amsterdam, Netherlands, Academic Medical Center, Amsterdam, Netherlands

4563/5 – Antibody targeting of anaplastic lymphoma kinase induces cytotoxicity of human neuroblastoma Erica L. Carpenter¹, Elizabeth A. Haglund¹, Adrian K. Chow¹, Andrew C. Wood¹, Lili T. Belcastro¹, James G. Christensen², Marc Vigny³, John M. Maris¹, Mark A. Lemmon⁴, Yael P. Mosse¹. ¹Children’s Hospital of Philadelphia, Philadelphia, PA; ²Pfizer Global Research and Development, La Jolla, CA; ³INSERM, Paris, France; ⁴University of Pennsylvania, Philadelphia, PA Poster Session

LB-366/11 – Patient-derived EBV-immortalized B-lymphocytes are a dominant contaminant of in vitro cultured human neuroblastoma tumor-initiating cells isolated from bone marrow. Sven Påhlman, Sofie A. Johnsson, Alexander Pietras, Caroline Wigerup, Ingrid Øra, Michael Andäng, Kenneth Nilsson, Tor Olofsson, David Gisselsson. Lund Univ., Malmö, Sweden, Lund Univ., Lund, Sweden, Karolinska Institute, Stockholm, Sweden, Uppsala Univ., Uppsala, Sweden Late-Breaking Poster Session

742/26 – Mechanisms of resistance to small molecule inhibition of anaplastic lymphoma kinase in human neuroblastoma Erica L. Carpenter¹, Elizabeth A. Haglund¹, Adrian K. Chow¹, James G. Christensen², John M. Maris¹, Yael P. Mosse¹. ¹Children’s Hospital of Philadelphia, Philadelphia, PA; ²Pfizer Global Research and Development, La Jolla, CA Poster Session

3942/29 – A pilot trial testing the feasibility of using molecular-guided therapy in patients with refractory or recurrent neuroblastoma Giselle L. Saulnier Sholler¹, Javed Kahn², William Ferguson³, Genvieve Bergendahl¹, Erika Currier¹, Shannon Lenox¹, Jeffrey Bond¹, William Roberts⁴, Deanna Mitchell⁵, Don Eslin⁶, Jacqueline Kraveka⁷, Joel Kaplan⁸, Nehal Parikh⁹, Suman Malempati¹⁰, Gina Hanna¹¹, Barton Kamen¹², Craig Webb¹³. ¹University of Vermont, Burlington, VT; ²National Institute of Health, Bethesda, MD; ³St. Louis University School of Medicine, St. Louis, MO; ⁴University of California San Diego School of Medicine, San Diego, CA; ⁵Michigan State University, Grand Rapids, MI; ⁶MD Anderson Cancer Center Orlando, Orlando, FL; ⁷Medical University of South Carolina, Charleston, SC; ⁸Levine Children’s Hospital, Charlotte, NC; ⁹Connecticut Children’s Medical Center, Hartford, CT; ¹⁰Oregon Health & Science University, Portland, OR; ¹¹Inova Fairfax Hospital for Children and Women, Falls Church, VA; ¹²Cancer Institute of New Jersey, New Brunswick, NJ; ¹³Van Andel Research Institute, Grand Rapids, MI Poster Session

1558/6 – Paracrine signaling through Mycn enhances tumor-vascular microenvironment in neuroblastoma Yvan H. Chanthery, W. Clay Gustafson, William A. Weiss. UCSF, San Francisco, CA Poster Session

4350/18 – Translating diagnostic gene expression profiles for pediatric solid tumors Daniel H. Wai¹, Michele R. Wing², Kelley Kneile², Yvonne Moyer², Jonathan D. Buckley³, Robert C. Seeger⁴, Douglas S. Hawkins⁵, Stephen X. Skapek⁶, Timothy J. Triche⁴. ¹Center for Personalized Medicine, Los Angeles, CA; ²The Research Institute at Nationwide Children’s Hospital, Columbus, OH; ³University of Southern California, Los Angeles, CA; ⁴Children’s Hospital Los Angeles, Los Angeles, CA; ⁵Seattle Children’s Hospital, Seattle, WA; ⁶University of Chicago, Chicago, IL Poster Session

5237/25 – Development of organ-selective neuroblastoma cell lines to identify genes mediating bone marrow and liver colonization Zillan Neiron¹, Kacper Jankowski¹, Jayne Murray¹, Sophia Champion², Murray D. Norris¹, Michelle Haber¹, Jamie I. Fletcher¹. ¹Children’s Cancer Institute Australia, Randwick, NSW, Australia; ²University of New South Wales, Kensington, NSW, Australia Poster Session

130/14 – MiR-204 acts as a tumor suppressor in neuroblastoma through down-regulation of the neurotrophic receptor TrkB Jacqueline M. Ryan¹, Amanda Tivnan¹, Isabella Bray¹, Joanna Fay¹, Andrew M. Davidoff², Lorraine Tracey², Raymond Stallings¹. ¹Royal College of Surgeons in Ireland & National Children’s Research Centre, Dublin, Ireland; ²St. Jude Children’s Research Hospital, Memphis, TN Poster Session

4685 – Mechanistic guidance of ALK inhibition for the treatment of neuroblastoma Scott C. Bresler¹, Andrew Wood², Elizabeth Haglund², James Christensen³, John M. Maris², Mark A. Lemmon¹, Yael P. Mosse². ¹University of Pennsylvania School of Medicine, Philadelphia, PA; ²Children’s Hospital of Philadelphia, Philadelphia, PA; ³Pfizer Inc., La Jolla, CA Minisymposium

1808/28 – Neuroblastoma cell lines established from progressive disease that exhibit partial or multi drug resistance are highly sensitive to chimeric receptor scFv(ch14.18)-zeta mediated NK cell killing Diana Seidel¹, Anastasia Shibina², C. Patrick Reynolds², Winfried S. Wels³, Holger N. Lode¹, Nicole Huebener¹. ¹University Medicine Greifswald, Greifswald, Germany; ²Texas Tech University Health Sciences Center, Lubbock, TX; ³Chemotherapeutisches Forschungsinstitut, Georg-Speyer-Haus, Frankfurt, Germany Poster Session

508/4 – Signal transduction and activator of transcription (STAT) 3 is necessary for environment-mediated drug resistance Tasnim Ara¹, Rie Nakata¹, Hiroyuki Shimada¹, Ralf Buettner², Robert C. Seeger¹, Hua Yu², Richard Jove², Yves A. DeClerck¹. ¹USC/Children’s Hospital Los Angeles, Los Angeles, CA; ²Beckman Research Institute/City of Hope, Duarte, CA Poster Session

926 – Whole genome and transcriptome sequencing defines the spectrum of somatic changes in high-risk neuroblastoma Olena Morozova¹, Inanc Birol¹, Richard Corbett¹, Karen Mungall¹, Edward F. Attiyeh², Shahab Asgharzadeh³, Yongjun Zhao¹, Richard A. Moore¹, Martin Hirst¹, Steven Jones¹, Michael D. Hogarty², Sharon Diskin², Yael P. Mosse², Maura Diamond², Richard Sposto³, Lingyun Ji³, Daniela S. Gerhard⁴, Malcolm A. Smith⁴, Javed Khan⁴, Robert C. Seeger³, Marco A. Marra⁵, John M. Maris², the NCI TARGET Initiative. ¹Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada; ²Children’s Hospital of Philadelphia and University of Pennsylvania School of Medicine, Philadelphia, PA; ³Children’s Hospital of Los Angeles and Keck School of Medicine, University of Southern California, Los Angeles, CA; ⁴National Cancer Institute, Bethesda, MD; ⁵Genome Sciences Centre, BC Cancer Agency and Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada Minisymposium

1800/20 – 4-HPR (fenretinide) sensitizes human neuroblastoma cells for antibody-independent and ch14.18-mediated NK cell killing Anastasia Shibina¹, Diana Seidel², Srinivas Somanchi³, Holger N. Lode², Dean A. Lee³, C.Patrick Reynolds¹, Nicole Huebener². ¹Texas Tech Univ. Health Sciences Ctr., Lubbock, TX; ²University Medicine Greifswald, Pediatric Hematology/Oncology, Greifswald, Germany; ³The University of Texas MD Anderson Cancer Center, Houston, TX Poster Session

1423/15 – Effects of DFMO-based combination therapy in advanced stage neuroblastoma Dana-Lynn T. Koomoa, Ingo Lange, Andre S. Bachmann. University of Hawaii, College of Pharmacy, Hilo, HI Poster Session

TARGET Project Team Highlights: Neuroblastoma Javed Khan. National Insts. of Health, Bethesda, MD NCI/NIH-Sponsored Session

NIH15. The NCI Therapeutically Applicable Research to Generate Effective Treatments (TARGET) Initiative: Using Large-Scale Genomics to Identify Novel Therapeutic Targets for Childhood Cancers

Towards a personalized approach to pediatric cancer management: Neuroblastoma as an example John M. Maris. Children’s Hospital of Philadelphia, Philadelphia, PA Major Symposium
Recent Findings from Genomic Analyses of Tumors

5359/30 – Cytotoxicity of MLN8237 and SAHA in pediatric cancer cell lines Jodi Muscal¹, Kathy Scorsone¹, Jeffrey Ecsedy², Stacey Berg¹. ¹Baylor College of Medicine, Houston, TX; ²Millenium Pharmaceuticals, Inc., Cambridge, MA Poster Session

4756 – Exome sequencing of 81 neuroblastomas identifies a wide diversity of somatic mutation Trevor J. Pugh¹, Michael Lawrence¹, Carrie Sougnez¹, Gad Getz¹, Edward Attiyeh², Michael Hogarty², Sharon Diskin², Mosse Yael², Maura Diamond², Shahab Asgharzadeh³, Richard Sposto³, Jun S. Wei⁴, Thomas Badgett⁴, Wendy B. London⁵, Julie Gastier-Foster⁶, Malcolm A. Smith⁴, Daniela S. Gerhard⁴, Robert Seeger³, Javed Khan⁴, Matthew L. Meyerson¹, John M. Maris², NCI Therapeutically Applicable Research to Generate Effective Treatments (TARGET) Initiative. ¹The Broad Institute of MIT and Harvard, Cambridge, MA; ²Children’s Hospital of Philadelphia, Philadelphia, PA; ³Children’s Hospital of Los Angeles, Los Angeles, CA; ⁴National Cancer Institute, Bethesda, MD; ⁵Dana-Farber Cancer Institute and Children’s Oncology Group Statistic and Data Center, Boston, MA; ⁶Nationwide Children’s Hospital, Columbus, OH Minisymposium

Overview of environment: Mediated drug resistance Yves A. DeClerck. USC/Children’s Hospital Los Angeles, Los Angeles, CA Educational Session

Big antibody news

The “third generation” humanized anti-GD2 antibody with protein fusion of IL2 to the antibody has completed Phase I and II clinical trials for melanoma and neuroblastoma, and is now ready for use in Phase III clinical trials. The license for hu14.18-IL2 was just acquired by a small biotech in Vienna called Apeiron. The license was acquired from Merck.

Apeiron’s press release:

Apeiron Licenses Phase II/III Anticancer Ab-IL2 Fusion Protein from Merck KGaA

Long-term follow up of children with and without ch14.18/CHO in German trials NB90 and NB97

It has been a very long wait to finally see this graph. The Germans reported on this at ANR 2008 in Japan, and again at ANR 2010 in Stockholm.  See Graph A in Figure 2. “Follow-up analysis of the patient cohort indicated that immunotherapy with ch14.18 [no cytokines] may prevent late relapses.” Remember this group reported in 2004 “analysis failed to demonstrate an advantage of antibody treatment” –

http://jco.ascopubs.org/content/22/17/3549.long

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The statement about late relapses is a little puzzling to me. Graph A shows that “events” (which are usually relapses) occurred up until 10 years in both the ch14.18 and maintenance groups. Only the “no consolidation” group had later events.

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The authors concluded:”Today, the most effective way of antibody based maintenance therapy seems to be a combination immunotherapy with MAB ch14.18, cytokines, and retinoic acid. But these results need confirmation by at least another randomized trial. Further, metronomic low dose oral chemotherapy consolidation was found as effective as MAB ch14.18 consolidation in this retrospective analysis and, therefore, also warrants further evaluation. Prospective clinical trials must demonstrate if the concept of low dose metronomic chemotherapy is feasible and effective after ASCT and in combination with immunotherapy.”

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Since the early results did not show a benefit of ch14.18 without cytokines, and yet the COG trial showed 20% advantage in early results, it could be argued that there might be a big difference in survival between oral metronomic chemotherapy and ch14.18 with cytokines.

http://www.biomedcentral.com/content/pdf/1471-2407-11-21.pdf

Germans report on outcomes of relapsed NB patients who received three different regimens

Treatment and outcomes of patients with relapsed, high-risk neuroblastoma: Results of German trials.

Simon, T., Berthold, F., Borkhardt, A., Kremens, B., De Carolis, B. and Hero, B. (2011), Treatment and outcomes of patients with relapsed, high-risk neuroblastoma: Results of German trials. Pediatric Blood & Cancer, 56: 578–583. doi: 10.1002/pbc.22693

This is an important publication and was presented at ANR 2010. Few groups have tackled relapsed NB in any systematic way. Wendy London’s abstract presented at ASCO 2010 and ANR 2010 on survival after relapse suggests that some relapsed NB children are salvageable, and the Germans and Swedes are advancing understanding in treating relapse. This same approach looking at more aggressive measures for relapsed leukemia kids is how relapse protocols were developed to treat relapsed leukemias.

Drs John Maris and Yael Mosse awarded patent for ALK mutation link to diagnosis, prognosis, and treatment of neuroblastoma

Summary of patent:

CHK1 suspected to be a promising target in NB — inhibitors are being tested in adults

‎”CHK1 mRNA expression was higher in MYC–Neuroblastoma-related (MYCN)–amplified (P < 0.0001) and high-risk (P = 0.03) tumors.”

RNAi screen of the protein kinome identifies checkpoint kinase 1 (CHK1) as a therapeutic target in n

www.pnas.org

Edited by Stephen J. Elledge, Harvard Medical School, Boston, MA, and approved December 17, 2010 (received for review August 23, 2010)

Protein May Be Key to New Treatment in a Childhood Cancer — PHILADELPHIA, Feb. 7, 2011 /PRNewswire-

The neuroblastoma oral papers (OP2) presented on Friday October 22, 2010 at SIOP in Boston covered a range of topics including prognostic factors, targets, and stem cell contamination. This report will focus on the presentation on prognostic significance of segmental alterations in neuroblastoma tumors.

Accumulation of segmental alterations determines progression in neuroblastoma (O024)

Neuroblastoma tumor biology has long been an intense subject of study because of the heterogeneous nature of this disease. Looking at macro, micro, and genetic features reveals the differences in tumors, and why some children with neuroblastoma survive without treatment and others do poorly with the most intense treatments conceived. Now that technology is accessible to analyze genetic profiles, more precise risk can be assigned, and appropriate treatment given. Further, this analysis allows for understanding the evolution of tumor genetics as relapse and progression occurs.

Gudrun Schleiermacher from France presented on a study of numerical and segmental chromosome alterations in neuroblastoma tumors. This subject was a matter of interest at ANR in Stockholm as well, and this abstract was also presented at ASCO in June.[1]  This topic has been the subject of many abstracts at recent meetings, and several recent publications confirm the importance of this work [2-6].

Prior publication in 2009 from this French group included  a comprehensive overview of the genetic alterations of neuroblastoma and clinical significance. A series of 493 neuroblastoma samples was investigated by array-based comparative genomic hybridization and the analysis identified several types of profiles:

Tumors presenting exclusively whole-chromosome copy number variations were associated with excellent survival. No disease-related death was observed in this group. In contrast, tumors with any type of segmental chromosome alterations characterized patients with a high risk of relapse. The analysis of the overall genomic pattern, which probably unravels particular genomic instability mechanisms rather than the analysis of individual markers, is essential to predict relapse in NB patients. It adds critical prognostic information to conventional markers and should be included in future treatment stratification.[2]

Caren and collegues (Sweden) also concurred that these studies have:

implications for therapy in different risk groups and stresses that genome-wide microarray analyses should be included in clinical management to fully evaluate risk, aid diagnosis, and guide treatment. [5]

Schleiermacher and colleagues analyzed 394 neuroblastoma tumors with array-based comparative genomic hybridization and linked the results to clinical data for outcomes. The tumor samples included all risk groups, and analysis was performed again in the event of relapse to discover changes in the tumor profile. The study confirmed that neuroblastoma tumors are characterized by two distinct genetic profiles — either numerical or segmental chromosome alterations.

Tumors were first divided into five groups based on genomic aberrations: numerical only, segmental only, MYCN amplified, numerical and segmental, MYCN and numerical. The tumors with only numerical alterations had the best prognosis. No breakpoint pattern was observed in the segmental-only group which contained up to 1000 breakpoints. Seven or more breakpoints portended a worse prognosis, and was an independent factor in multivariate analysis. More breakpoints were correlated with higher age at diagnosis, higher stage of disease, and higher risk of relapse.

Tumors with only numerical alterations at diagnosis frequently acquired segmental alterations upon relapse. This could not be strictly attributed to chemotherapy since tumors treated with surgery only had acquired segmental aberrations. The authors concluded that tumor progression is directly linked to an accumulation of segmental alterations.

References

1. J Clin Oncol. 2010 Jul 1;28(19):3122-30. Epub 2010 Jun 1. Accumulation of Segmental Alterations Determines Progression in Neuroblastoma. PMID: 20516441

2. J Clin Oncol. 2009 Mar 1;27(7):1026-33. Epub 2009 Jan 26.  Overall genomic pattern is a predictor of outcome in neuroblastoma. PMID: 19171713

3. British Journal of Cancer (2007) 97, 238–246.  Chromosomal CGH identifies patients with a higher risk of relapse in neuroblastoma without MYCN amplification. [free fulltext]

4. Am J Pathol. 2010 Jun;176(6):2616-25. Epub 2010 Apr 15. 2p24 Gain region harboring MYCN gene compared with MYCN amplified and nonamplified neuroblastoma: biological and clinical characteristics. PMID: 20395439

5. Proc Natl Acad Sci U S A. 2010 Mar 2;107(9):4323-8. Epub 2010 Feb 9.  High-risk neuroblastoma tumors with 11q-deletion display a poor prognostic, chromosome instability phenotype with later onset. [free fulltext]

6. N Engl J Med 2005; 353:2243-2253.  Chromosome 1p and 11q Deletions and Outcome in Neuroblastoma. [free fulltext]

Travel to this meeting was supported by:

• Lighthouse Laboratories
• Max’s Ring of Fire
• Magic Water
• Friends of Will
• Solving Kids’ Cancer
• Children’s Neuroblastoma Cancer Foundation

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Swedish researchers share the prize at SIOP for winning posters on neuroblastoma

Drs Fredrik Hedborg (Uppsala University) and Catarina Trägar (Karolinska Institute) shared the top prize for neuroblastoma research poster at SIOP 2010.

PH036 Age dependent genotypes in high-risk neuroblastoma: MYCN amplification is a fast track to aggressive disease whereas segmental deletion of 11q implies a more complex, multi-step tumor evolution (p. 896)

Dr Hedborg and colleagues explored the age-dependence of the genetics of aggressive disease in 30 high-risk and 4 intermediate-risk children. MYCN amplification was present in all but one of the 12 youngest children (mean age 29.6 months, range 4 – 30 months) and MYCN amplification was absent in all but one of the 11 oldest (mean age 65.6 months, range 57 – 169 months), and 12/18 of these had 11q loss. This age differential was confirmed by the Swedish Childhood Cancer Registry where mean ages at diagnosis were 29.4 months for MYCN amplified (n=65)  and 54.8 months for MYCN-non-amplified (n=46). Significantly more segmental chromosome aberrations were noted in older children with 11q loss, and this data suggest that two major pathways exist in the development of aggressive neuroblastoma. MYCN-amplification tumors in younger children result from fewer but rapid genetic events, whereas tumors in older children with 11q loss are the result of a slower, multi-step process.

PH038 Differences in biological features and survival improvement between genetic subsets of high-risk neuroblastoma indicate the need of adapted treatment (p. 897)

Dr Trägar and colleagues also looked at Swedish registry data and noted older age for 34 children with 11q deletion (median age 41 months) and longer median survival of 40 months compared to children with MYCN-amplified tumors (median age 22.5 months, median survival 16 months), but both groups had similar 8 year overall survival rate of ~35%.

Survival data were reported as follows:
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The researchers concluded that 11q-deletion tumors present later than MYCN-amplified tumors, but noted that prognosis is similar, and suggest further consideration is needed for therapeutic approaches for 11q-deleted tumors since prognosis has not improved for this group since the 1980s.

Both research teams have contributed to increased understanding concerning the relationship between age and biology of neuroblastoma high-risk tumors.

Travel to this meeting was supported by:

• Lighthouse Laboratories
• Max’s Ring of Fire
• Magic Water
• Friends of Will
• Solving Kids’ Cancer
• Children’s Neuroblastoma Cancer Foundation

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History of ANR: Advances in Neuroblastoma Research

See photos posted on the ANR site!  http://www.anr2010.com/photos/5166/Page.aspx

Dr Audrey Evans initiated this meeting in 1974, and interestingly, this was the same year she helped found the first Ronald McDonald House in Philadelphia. Approximately 50 researchers and clinicians participated in that first ANR meeting. There was one abstract submitted on genetics/genomics that year.

This meeting has 600+ registrants from 37 countries who submitted 500+ abstracts. Over 200 abstracts are on genetics or genomics. This is also the largest pediatric oncology meeting that Sweden has ever hosted. There are 4 Nobel prize winners participating here in the “home” of the prize.

This year is also the 200th anniversary of the prestigious Karolinska Institute, founded as a training course for military surgeons in 1810 and now one of the premiere medical research institutions in the world.

Update on ALK mutations and implications for treatment

The first day offered an update course on neuroblastoma as well as the welcome ceremonies. A significant focus was on genome wide association studies which describe the association of mutations with incidence of neuroblastoma, as well as potential prognostic information, cell origin,  and new targets. The technology is rapidly expanding to produce more data, and the cost is falling. Eventually the most expensive part will be the data handling. This technology is extremely important for the future of NB diagnosis and treatment. The landmark discoveries of the ALK mutation (and previously known PHOX2b mutation) from Dr Maris’ lab has provided strong evidence that neuroblastoma is not associated with environmental factors, but rather a “perfect storm” of genetic mutations. Since some of these mutations have functional implications, they can serve as targets for treatment, as in the case of the ALK inhibitor. As the mutations are further described, it may be possible to more accurately identify those intermediate risk cases that require more treatment, and the ultra-high risk cases that are likely to fail front- line therapy, allowing for new treatment strategies for that group.

Dr Yael Mosse presented the clinical relevance of ALK mutations, and elucidated the significance of hereditary features, target potential, and future possibilities. At this point they have found in familial NB cases ~80% have ALK mutations and ~10% have PHOX2B mutations. A variety of other genes will likely describe the remaining 10%.

Out of 1148 NB cases including all risk categories, 7.3% were found to have ALK mutation. But in older children (10 years old or older at diagnosis) the proportion is higher at 17%. To date over 20 ALK mutations have been discovered, but there are three “hot spots” and of those, R1275Q (~42%) and F1174L (~17%) are the most common.

In today’s plenary session Yael Mosse discussed “Exploitation of ALK as a therapeutic target in neuroblastoma” and explained that they found 11.5% of MYCN amplified tumors have ALK mutations, as well as 8.8% of all high risk.

The most significant and surprising issue is that after this mutation was discovered in NB, a drug happened to be already available to target this mutation (previously found in lung cancer). To date several NB children with ALK mutation have been enrolled on the trial and while it is too early to guess at the potential for responses, it is encouraging to know there is already an antibody suggested for use in overcoming any possible acquired resistance.