Anti-ALK antibody explored at Children’s Hospital of Philadelphia

An increasingly important research topic in neuroblastoma focuses on anaplastic lymphoma kinase (ALK) mutation or expression. At AACR there were 8 presentations on ALK and NB. While efforts are ongoing to better target the ~7% of NB cases that have an ALK mutation, now there is also compelling research on the ALK protein expression which is found in 90% of NB cases. ALK expression is found in some cancers (primary lymphoma) and is detected using monoclonal antibodies. In normal tissues, ALK protein is expressed in only a few cells within the developing and mature nervous system (glial cells, neurons, endothelial cells and pericytes).[1]

Dr Max van Noesel from Erasmus MC-Sophia Children’s Hospital, Rotterdam, Netherlands presented interesting data showing that the percent of NB cells in a tumor sample that are positive for ALK protein expression correlate with outcome and risk stratification. His team examined 71 NB cases (all risk categories) for ALK expression, and found that tumor samples that showed 75-100% positive cells for ALK expression had the worst outcome,  and that response to the ALK inhibitor TAE684 was dependent on higher ALK expression. Tumors with ALK mutation had higher ALK protein expression and responded better to in vitro testing of the ALK inhibitor.[2]

Meanwhile, Dr Erica Carpenter, a researcher in Dr Yael Mosse’s lab at CHOP, examined targeting NB cells with anti-ALK antibody. Given that the worst NBs express the ALK protein, this is a compelling idea for several reasons. Although this work is still in early preclinical stage, researchers will be seeking to answer many questions including– could this antibody strategy be more effective than anti-GD2 antibodies? Could this therapy present less toxicity?

Dr Carpenter also explored the combination of anti-ALK antibody with the ALK inhibitor PF-02341066 in NB cell lines, and found that the combination is more effective than either agent alone because the ALK inhibitor drives up ALK protein expression on the NB cell surface:

Therefore, we hypothesized that antibody targeting of ALK in neuroblastoma was a therapeutically appropriate strategy. To first confirm the potential of anti-ALK antibody-mediated immunotherapy, we used in vitro assays to demonstrate enhanced immune-cell induced cytotoxicity of antibody-treated human neuroblastoma-derived cell lines. We next showed that in vitro antibody treatment of neuroblastoma cell lines expressing activated ALK led to growth inhibition and cell death. These effects were enhanced by treatment with PF-02341066, an orally available small-molecule inhibitor of the ALK tyrosine kinase. To identify the mechanism behind this enhanced combined effect, we used flow cytometry to show that PF-02341066 sensitizes cells to antibody treatment by inducing accumulation of cell-surface ALK, thus increasing the accessibility of antigen for antibody binding. Finally, to further predict in vivo cytotoxic mechanisms of dual ALK targeting, we used flow cytometry to demonstrate enhanced apoptosis and proliferation inhibition resulting from combined antibody and inhibitor treatment as compared to either drug alone.[3]

The next step in this exciting project is developing a clinical grade antibody, which is underway, and after further preclinical testing, the agent will be ready for clinical trials.

References

1. http://www.nordiqc.org/Epitopes/ALK1/ALK1.htm
2. Anaplastic lymphoma kinase (ALK) expression is an independent prognostic factor in neuroblastoma patients and correlates well with ALK inhibitor response in vitro
3. Antibody targeting of anaplastic lymphoma kinase induces cytotoxicity of human neuroblastoma

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-

Neuroblastoma bits from November 2010

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NCI featured article on ALK inhibitor Crizotinib

While encouraging responses are being seen in lung cancer patients with ALK mutation, drug resistance is expected to be a problem.

Crizotinib Continues to Show Promise for Some Lung Tumors, Faces Challenge of Drug Resistance

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FDA discusses Crizotinib pediatric trial design

Pediatric Oncology Subcommittee of the Oncologic Drugs Advisory Committee (ODAC) Nov 30, 2010

“If the current COG Phase I/II studies evaluating crizotinib in refractory pediatric solid tumors or ALCL shows promising activity in neuroblastoma, should crizotinib be evaluated in the post-transplant relapsed/refractory setting or should a randomized trial in a less heavily treated population be considered? If the former population (i.e., post-transplant relapsed or refractory) is a more appropriate setting, please discuss whether Progression Free Survival (PFS) is an adequate endpoint.”

Committee discussion questions

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Insight Genetics Awarded Qualifying Therapeutic Discovery Program Grant

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http://www.eurojournals.com/ejsr_40_1_15.pdf

www.eurojournals.com

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Scientific American describes the recent advances in viruses that kill cancer — now available to children this year for the first time –

Cancer Therapy Goes Viral: Progress Is Made Tackling Tumors with Viruses: Scientific American

“A new generation of oncolytic viruses are entering late-stage clinical trials, repurposing smallpox and herpesvirus to take on tough tumors.”

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Search goes on for toxins to kill neuroblastoma

“Luesch is experimenting with toxins—drawn from several species of cyanobacteria—on several types of cancer, including neuroblastoma, a childhood disease that attacks nerve cells. In July 2009, he launched a four-year, $1.2 million NCI-funded study, part of which entails… largazole testing on mice.”

Why Scientists Are Searching for Cures Underwater – Newsweek

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Childhood cancer survival in Australia

“Survival outcomes using the period method for 11903 children diagnosed with cancer between 1983 and 2006 and prevalent at any time between 1997 and 2006. The overall relative survival was 90.4% after 1 year,  79.5% after 5 years and 74.7% after 20 years.”

Population-based survival estimates for childhood cancer in Australia during the period 1997–2006

www.nature.com

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Accutane (cis-retinoic acid or isotretinoin) and depression?

A child with neuroblastoma is far more more often a preschooler than a teen. So the risk of suicide and depression is unlikely with such small children. It is a concern with the few teens and young adults with neuroblastoma on this drug, especially since the dosing is 2 to 10 times higher than what is prescribed for acne, and the lower dose is the basis for all the previous studies looking at incidence of depression and suicide. This small study gives important evidence that the drug may not contribute entirely to increased risk:

Severe Acne Linked to Suicide Risk Even Before Treatment Is Started

cme.medscape.com

In a retrospective Swedish cohort, suicide attempts were associated with severe acne even before treatment with isotretinoin was started.

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Recap of presentations

I have so much more to report on ASCO and ANR (coming soon), but should share information about this conference first. This year’s conference was exceptional.  The presentations covered a wide range of important topics, and I am convinced the 130 parents in attendance walked away with essential information for their families. This conference is extraordinary in that no rare disease organization provides such a quality forum for education by top experts in the field—for free, including hotel, meals, children’s program, bereavement session, and even transportation costs for those with the greatest need.  I have met attendees from Australia, Turkey, and other nations. This concept is unprecedented, and CNCF president Pat Tallungan works incredibly hard at the challenge to raise funds for this conference every year. CNCF accepts and appreciates donations for this conference (see www.nbhope.org ).

Dr Yanik in particular expressed his amazement at the difficult and insightful questions posed by the parents. I was struck by the contrast I had just seen at the ASCO and ANR meetings. Attendees come in and out during presentations, and often no questions are asked so no discussion ensues. I was amazed at how many researchers travel great distances to give five minute presentations, or just show a poster. The presenters at this conference spoke for at least 30 minutes and appreciated a very attentive audience. The impact is significant in that parents learn first hand from experts about this disease, and are exposed to information about new treatments which can facilitate quick enrollment on trials.

Speakers and topics were:

Susan Cohn ~ Overview of Neuroblastoma and Intermediate Risk Study

Yael Mosse ~  ALK inhibitor, Aurora A Kinase inhibitor, and ABT-751 Update

Giselle Sholler ~  Update on NMTRC Trials

Patrick Reynolds ~ Adult Oncology Connection/Update on Fenretinide trial

Shakeel Modak ~   3F8, NK Cell Therapy, and 8H9 Update

Sandeep Soni ~  Reduced Intensity Allogeneic Transplant

Kate Matthay ~   Overview of NANT trials

Peter Zage ~  3F8/Accutane Randomized Trial (national)

Greg Yanik ~  MIBG Scoring/Ultratrace Trials

Michael Burke ~  Oncolytic Virus Trial

Melissa Alderfer ~   Post Traumatic Stress Syndrome

David Salsberg ~  Neuropsych/learning issues facing NB Children

A few presentations will be covered in each post.

Overview of neuroblastoma and intermediate risk study update

Dr Sue Cohn gave a great overview on neuroblastoma and an update on the current intermediate risk study ANBL0531 (see http://clinicaltrials.gov/ct2/show/NCT00499616 ). This study opened in 2007, is enrolling at 180 locations, and will accrue 395 children. Intermediate risk is a challenging group to design studies for. The numbers are small, with approximately 10-20% of all neuroblastomas diagnosed as intermediate risk. This means there are roughly 100 intermediate risk children diagnosed each year in the US. The past and current studies are complex, with multiple treatment arms depending on tumor characteristics and response to therapy. This study includes 2, 4, or 8 cycles of outpatient (medium dose) chemotherapy, and cis-retinoic acid (Accutane) for some children. The goal is to accurately assign children to the right treatment arm and see if reducing therapy for some children will result in the same overall high survival seen in previous studies.

ALK inhibitor, Aurora A Kinase inhibitor, and ABT-751 updates

Dr Yael Mosse spoke about the research at CHOP (Children’s Hospital of Philadelphia) on ALK mutation and the remarkable speed in which a trial (ADVL0912) was opened to treat children with a drug already available for the mutation in lung cancer. The drug PF-02341066 now has a name, crizotinib. So far 5 children with NB with ALK aberration have been enrolled, and 5 with other diseases.  Dr Mosse shared some of the same information presented at both ASCO and ANR (see previous post on ALK).

The aurora A kinase inhibitor MLN8237 trial COG-ADVL0812 is closed now that the phase I is complete. The data is under review to determine if the drug is active against neuroblastoma for those who enrolled (11 NB children) on the phase I portion of the trial.  If so, the phase II trial will open for neuroblastoma only. In mice, striking synergy is seen with this inhibitor when combined with irinotecan and temozolomide. This combination is planned for an upcoming new NANT (New Approaches to Neuroblastoma Therapy) trial N09-03 directed by Steven DuBois.

A phase II trial of ABT-751 ran from 2007 to 2009 and accrued 91 children. The response data will be released at the fall COG (Children’s Oncology Group) meeting. Right now compassionate access is open at CHOP for second remission.

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.