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This Week in Pediatric Oncology Episode 3

1:24 Maureen O’Brien, MD discusses “Increased risk of vincristine neurotoxicity associated with low CYP3A5 expression genotype in children with acute lymphoblastic leukemia” in Pediatr Blood Cancer. 2011 Mar;56(3):361-7. doi: 10.1002/pbc.22845. Epub 2010 Nov 11.

http://www.ncbi.nlm.nih.gov/pubmed/21225912

22:10 Lars Wagner, MD discusses “Phase II study of irinotecan and temozolomide in children with relapsed or refractory neuroblastoma: a Children’s Oncology Group study” from J Clin Oncol. 2011 Jan 10;29(2):208-13. Epub 2010 Nov 29.

http://www.ncbi.nlm.nih.gov/pubmed/21115869

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Four oncolytic virus trials open at Cincinnati Children’s for pediatric solid tumors

Dr Tim Cripe provided a very helpful comparison chart for the oncolytic virus trials currently open at Cincinnati Children’s, and permission to post it. To open a PDF of the chart, click on this link:

Viral study comparison (PDF document)

The chart lists the similarities and differences of the four oncolytic virus trials:  SVV-001 (NTX-010 or seneca Valley virus), HSV1716 (Herpes simplex), JX-594 (Jennerex vaccina), and Reolysin (reovirus).

Regarding age, the HSV1716 is open for ages 13 to 30, whereas the others are for 2 or 3 years up to 21. Both SVV-001 and Reolysin are given intravenously, whereas HSV1716 and JX-594 are given intratumoral (injected into the tumor).

HSV1716 and JX-594 require short inpatient stays, but Reolysin and SVV-001 are give outpatient. The SVV-001 is given in a single dose (one-hour infusion), whereas the JX-594 and HSV1716 can be administered to tumor sites every 28 days up to four times, and Reolysin is given in a one-hour infusion for five days, and this is repeated every 28 days for up to 12 months.

The chart also lists the current dose levels for each trial (all are phase I studies).

The SVV-001 and Reolysin are open in several COG Phase I centers, and the HSV1716 and JX-594 are only open at Cincinnati Children’s, and that is the only location that has all four trials open. Only the Reolysin trial restricts eligibility to those who have not had prior oncolytic viruses, so it is possible to enroll on these trials in sequence.

For more background on oncolytic virus trials for children, see the following links.

Review article: http://www.nbglobe.com/2010/11/19/status-on-oncolytic-virus-therapies-for-pediatric-solid-tumors/

Webinar: http://www.nbglobe.com/2011/01/26/webinar-on-oncolytic-viruses-for-children/

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This Week in Pediatric Oncology Episode #2:

Host Dr Tim Cripe interviews Dr Greg Reaman, outgoing chair of the Children’s Oncology Group

Sponsored by Solving Kids’ Cancer (with NB Globe support), posted with permission

In this second episode of TWiPO, host Dr Tim Cripe interviews Dr Gregory Reaman about his career in pediatric oncology, leadership of the COG, challenges, and expectations for the future.

TWiPO Episode 2: Interview with Dr Greg Reaman

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Podcast launch about new advances for childhood cancer

Solving Kids’ Cancer (with NB Globe support) is sponsoring a free podcast series for researchers, clinicians, advocates, and others focusing on pediatric cancer research, hosted by physician-scientist Dr Timothy Cripe and colleagues at Cincinnati Children’s. Podcasts will be published 2 to 4 times per month with discussions on new publications, clinical trials, interviews with thought leaders, and more. All inquiries, ideas, and comments are welcome and can be sent to twipo@solvingkidscancer.org This first episode is a discussion among the pediatric oncologists about the recently published paper in Journal of Clinical Oncology “Outcomes for Children and Adolescents With Cancer: Challenges for the Twenty-First Century” (J Clin Oncol 28:2625-2634) [free fulltext]   TWiPO Episode 1 Feb 28 Host and Co-Hosts (click on photos for bios):

Timothy P. Cripe, MD, PhD

Maureen M. O'Brien, MD, MS

Lars M. Wagner, MD

Rajaram Nagarajan, MD, MS

James I. Geller, MD

TWiPO Episode #1: Feb 28, 2011  Epidemiology of Childhood Cancer

• 0:00 – Intro
• 5:44 – Paper: Outcomes for Children and Adolescents With Cancer: Challenges for the Twenty-First Century (J Clin Oncol 28:2625-2634.)
• 6:45 – Incidence (increase for some cancers)
• 12:05 – Cause
• 14:43 – Mortality rates declined
• 16:35 – Disease specific rates – leukemia
• 25:16 – Brain tumors
• 26:35 – Sarcomas
• 33:14 – Germ cell/liver/Wilms
• 36:15 – Neuroblastoma
• Conclusion

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Posted with permission.

The content of this presentation is a recitation of general scientific principles, intended for broad and general physician understanding and knowledge and is offered solely for educational and informational purposes as an academic service of Cincinnati Children’s Hospital Medical Center.   The information should in no way be considered as offering medical advice for a particular patient or as constituting medical consultation services, either formal or informal.   Nothing in the content of this presentation pertains to any specific patient and the dissemination of such general information does not in any way establish a physician-patient relationship nor should the information be considered, or used, as a substitute for medical diagnosis or treatment.  The recipient must use their independent judgment in determining the value and use of the information contained herein and its application to a situation.  The presenter expressly disclaims any decision-making authority or supervisory control over the recipient.  The content of this presentation does not constitute either an explicit or implicit consent or contract by any physician or other employee of Cincinnati Children’s Hospital Medical Center to create a physician-patient relationship and such information in no way creates, substitutes or in any way consists of examination, diagnosis, treatment or the prescription of treatment for any patient.  No information provided herein shall create a warranty of any type nor shall any person rely on any such information or advice.

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

13 young researchers each receive $750K

Stand Up To Cancer (SU2C) announced April 4, 2011 the second round of awards for its Innovative Research Grants Program (IRG), and named the 13 young scientists that will receive a combined total of $9.74 million over the grants’ three-year term to conduct high-risk/high-reward translational cancer research.

In 2009 the first set of 13 awards included 7 projects directed to pediatric cancer research, and this year 2 of the 13 recipients are working on pediatric leukemias, but none with focus on neuroblastoma or pediatric solid tumors which have poor prognosis.

The 13 Stand Up To Cancer Innovative Research Grant recipients for 2011 are:

• Yali Dou, Ph.D., University of Michigan: Targeting MLL in Acute Myeloid Leukemia
• Adolfo A. Ferrando, M.D., Ph.D., Columbia University Medical Center: Targeting Genetic and Metabolic Networks in T-ALL
• Estela Jacinto, Ph.D., University of Medicine & Dentistry of New Jersey – Robert Wood Johnson Medical School: Targeting Protein Quality Control for Cancer Therapy
• Mei Kong, Ph.D., Beckman Research Institute of the City of Hope: Targeting PP2A and the Glutamine-Sensing Pathway as Cancer Treatment
• Dr. Hui Li, Ph.D., University of Virginia: Chimeric RNAs Generated by Trans-splicing and Their Implications in Cancer
• Dr. Roger S. Lo,* M.D., Ph.D., UCLA’s Jonsson Comprehensive Cancer Center: Exome Sequencing of Melanomas with Acquired Resistance to BRAF Inhibitors (recipient of the Allan H. (Bud) and Sue Selig Stand Up To Cancer M Melanoma Innovative Research Grant
• Charles G. Mullighan, M.D., St. Jude Children’s Research Hospital: Identification and Targeting of Novel Rearrangements in High-risk ALL
• Dana Pe’er, Ph.D., Columbia University: A Systems Approach to Understanding Tumor Specific Drug Response
• Sridhar Ramaswamy, M.D., Massachusetts General Hospital: Targeting Sleeping Cancer Cells
• Eric Alejandro Sweet-Cordero, M.D., Stanford University: Inhibiting Innate Resistance to Chemotherapy in Lung Cancer Stem Cells
• Amy J. Wagers, Ph.D., Joslin Diabetes Center: Developing New Therapeutic Strategies for Soft-tissue Sarcoma
• Angelique W. Whitehurst, Ph.D., The University of North Carolina at Chapel Hill: Framing Therapeutic Opportunities in Tumor-activated Gametogenic Programs
• Catherine J. Wu, M.D., Dana-Farber Cancer Institute: Coupled Genetic and Functional Dissection of Chronic Lymphocytic Leukemia

A call for Letters of Intent was issued October 2010. The Innovative Research Grants Committee (38 members) considered 188 eligible letters in an evaluation process that began in January 2011. These were narrowed down and 43 full research proposals were submitted. From that group, the committee selected the 13 recipients.

The committee evaluated the submissions using these criteria:

• potential for high-risk/high-reward;
• innovation in method or approach;
• potential for significant translation to clinical application;
• promise to improve and save the lives of patients with cancer;
• and potential to develop into a Dream Team project at a later time.

Pediatric oncologists and researchers on the review committee include Dr John Maris (Children’s Hospital of Philadelphia) and Dr Lee Helman (NCI intramural scientist who studies pediatric sarcomas).

In the last cycle, Dr Charles Roberts from Dana-Farber Cancer Institute identified a new druggable target for a rare pediatric cancer rhabdoid tumor (not applicable to neuroblastoma but present in some percent of other adult tumors) and a drug company is interested in pursuing this target:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2763035/

The Roberts laboratory is interested in the role of dysfunctional chromatin remodeling in the genesis of cancer. It is increasingly clear that epigenetic modifications play a critical role in the development of cancer.  The SWI/SNF complex, which utilizes ATP hydrolysis to remodel chromatin, has a potent tumor suppressor role.  Several of its subunits are specifically mutated in a variety of lethal human cancers including those of lung and breast as well as childhood cancers.  Accumulating evidence has revealed a role for the complex in epigenetic regulation via nucleosome remodeling based control of lineage-specific transcription.  Indeed, we have demonstrated key roles for SNF5, a core member of this complex, in tumor suppression using genetically engineered mouse models. Inactivating mutations in the SNF5 gene result in aggressive cancers in children and a familial cancer predisposition syndrome. We hypothesize that Snf5 is a master regulator of gene expression via its effects on chromatin structure and seek to identify the mechanisms by which perturbation of this ATPase chromatin remodeling complex leads to cancer formation. Given the dramatic nature in which inactivation of SNF5 drives cancer formation, characterization of this complex will lead to insights into the mechanisms of tumorigenesis. Thus, we are using mouse modeling combined with molecular, cellular and biochemical approaches to characterize this newly appreciated mechanism of tumor suppression and to identify novel therapeutic targets.

http://charlesrobertslab.dfci.harvard.edu/

The Roberts laboratory is interested in the role of dysfunctional chromatin remodeling in the genesis of cancer. It is increasingly clear that epigenetic modifications play a critical role in the development of cancer.  The SWI/SNF complex, which utilizes ATP hydrolysis to remodel chromatin, has a potent tumor suppressor role.  Several of its subunits are specifically mutated in a variety of lethal human cancers including those of lung and breast as well as childhood cancers.  Accumulating evidence has revealed a role for the complex in epigenetic regulation via nucleosome remodeling based control of lineage-specific transcription.  Indeed, we have demonstrated key roles for SNF5, a core member of this complex, in tumor suppression using genetically engineered mouse models. Inactivating mutations in the SNF5 gene result in aggressive cancers in children and a familial cancer predisposition syndrome. We hypothesize that Snf5 is a master regulator of gene expression via its effects on chromatin structure and seek to identify the mechanisms by which perturbation of this ATPase chromatin remodeling complex leads to cancer formation. Given the dramatic nature in which inactivation of SNF5 drives cancer formation, characterization of this complex will lead to insights into the mechanisms of tumorigenesis. Thus, we are using mouse modeling combined with molecular, cellular and biochemical approaches to characterize this newly appreciated mechanism of tumor suppression and to identify novel therapeutic targets

Neuroblastoma and Medulloblastoma Translational Research Consortium (NMTRC) moves to Grand Rapids, Michigan May 2, 2011

Dr Sholler completed medical school at New York Medical College, in Valhalla, NY. She was a resident in pediatrics and a fellow in pediatric hematology/oncology at Brown University before moving to the University of Vermont in 2005. Her research focuses on new therapies for neuroblastoma and medulloblastoma.

She describes her transition to new her position at Van Andel Research Institute (VARI) in an interview at AACR:

1.  Would you describe your new role at VARI, and continuing responsibilities at the University of Vermont and the NCI?

I will be Pediatric Oncologist, Spectrum Health Medical Group, Helen DeVos Children’s Hospital, Directing the Pediatric Oncology Therapeutic Discovery Clinic, focusing on NB and MB patients enrolling on our NMTRC trials and profiling all patients diagnosed with cancer and all relapses; Co-Director of the VARI/TGen Pediatric Oncology Research Program; and Associate Professor of the Neuroblastoma Translational Research Laboratory at Van Andel Research Institute. I will have a faculty appointment within Michigan State University’s College of Human Medicine.  I will continue as adjunct faculty at University of Vermont to continue key collaborations studying genomic profiles in neuroblastoma patients (with Jeff Bond) and work in Phage-display creating individualized antibodies (with David Krag).  I will continue as a Guest Researcher in the Pediatric Oncology Branch at the NCI where we will open the molecularly-guided protocol and I will be seeing NB patients in clinic monthly.

2.  How will this move enhance your goals for your research?
The Van Andel Research Institute is providing significant support and infrastructure to our research and consortium with a 5 year commitment.  The resources and collaboration at the Van Andel (with Craig Webb) and NCI (with Javed Khan and Melinda Merchant) has allowed this research to move forward, especially in the area of molecularly-guided therapy. I am thankful to have such a great team around us and this move will allow the research to flourish at an even faster rate.  Our goal are to bring understanding to each patients tumor and direct therapies to them as well as making promising new drugs available to kids with NB and MB.

3. During your time in Vermont, much has been accomplished. What is the most satisfying to you?
During my time in Vermont I have seen the creation of a new consortium  and the  bringing together of families and researchers for a common goal. It has been incredible to be a part of this evolving from nothing and out of many people caring about these children.  I am most satisfied to have been able to help many children in bringing them new therapies, I know that from this we will be able to improve the lives of kids with neuroblastoma.

4.  How will your move to VARI affect the operations of the NMTRC?
The Van Andel will now be the lead administrative site for the NMRTC, providing us with significant infrastructure which was minimal before and supported by family foundations. Now that money can go directly to supporting new research and trials. Dr. Jeff Trent, President and Research Director fo the Van Andel Research Instittue and TGen is devoted to making a difference in pediatric cancer and with his support and guidance I am excited about the possibilities of what we can do.

5.  Could you provide an update on the personalized medicine program you initiated?
We have completed our pilot study of molecularly-guided therapeutics showing it is possible in real-time to perform a biopsy, run a gene chip, analyze this using computer algorithms, hold a national tumor board to discuss the patient and create individual treatment plans in less than 2 weeks. We now have FDA approval for  a treatment study and IRB approval at 5 centers (DeVos Children’s Hospital, NCI, St. Louis Univeristy, Levine Children’s, and MDAnderson Orlando) and will be opening this trial in May 2011 when I arrive at the Van Andel.

Symposium for parents and researchers June 23 at VARI

Van Andel Research Institute and the NMTRC welcome all parents, foundations, scientists, and on physicians to attend the third symposium for progress and project updates on June 23rd, 2011 and more details will be forthcoming on the NMTRC site.

Poster presentation by Dr Sholler and colleagues at AACR 2011:

A pilot trial testing the feasibility of using molecular-guided therapy in patients with refractory or recurrent neuroblastoma