Two meetings of great interest are back-to-back this month. Unfortunately NB Globe will not be able to report first-hand on the Pediatric Cancer Translational Genomics Conference Feb 6-8 but news from a science writer employed to report on this meeting will be available — see the agenda here: https://www.tgen.org/tpcg/agenda.cfm

Following this is an exciting meeting on neuroblastoma is taking place in Tubingen, Germany Feb 16-18, and thanks to our supportive friends, The Neuroblastoma Children’s Cancer Alliance UK, reports on this meeting from NB Globe are forth coming!  Anyone interested is invited to attend an informal debriefing in London on Sunday afternoon/evening February 19 in Gloucester Road/Piccadilly line tube station area (contact here for more information about the place and time).

Bios of the speakers are found at this link: http://www.neuroblastoma2012.com/Speakers.php

A preview of topics:

Wednesday, February 15 ^th , 2012

Thursday, February 16 ^th , 2012

Friday February 17 ^th , 2012

Saturday February 18 ^th , 2012

LONDON — November 7, 2011 — A new clinical trial testing ¹⁷⁷Lutetium-DOTATATE (LuDO) for relapsed neuroblastoma is due to start in the UK next year. The UK is the first country to plan a clinical trial for this new molecular radiotherapy treatment for treating relapsed high-risk neuroblastoma, although it is already used to treat rare adult neuro-endocrine cancers.

Neuroblastoma is the most common ‘solid’ cancer diagnosed in babies and children. It accounts for around 15 percent of cancer deaths in children and around 100 children are diagnosed every year in the UK. Of these 100, approximately half will have high risk disease and the long term survival rate for these patients is less than 40 percent.

A pilot study that was given funding by the Neuroblastoma Children’s Cancer Alliance, a charity that helps children and families affected by neuroblastoma, has investigated a new radiotherapy treatment that targets a particular receptor on neuroblastoma cells. Dr Jenny Gains presented the promising results of the of this pilot study at the Neuroblastoma Children’s Cancer Alliance parents’ meeting July 23, 2011 in London.

Following the success of the pilot study, a three-year Phase II clinical trial is expected to start in the UK in early 2012. During the trial, the new radiotherapy treatment will be offered to all UK patients who meet the eligibility criteria – primarily patients who have relapsed neuroblastoma. Although it is a UK-wide trial, the treatment itself will take place at the Royal Marsden and University College Hospital (UCH) in London.

The pilot was carried out by a team of researchers, including Dr Mark Gaze, Consultant Clinical Oncologist at UCH and Great Ormond Street and Dr Jenny Gains, Clinical Research Fellow at UCH . Six children were offered the new radiotherapy treatment, of which five were found to have stable or improved disease following treatment.

Currently the targeted radiotherapy treatment offered to neuroblastoma patients is a compound called ¹³¹I-mIBG. However, this treatment has various limitations as some neuroblastoma cells do not have the receptors which this compound attaches to, so will not be killed by this treatment. Also ¹³¹I-mIBG can have serious side effects for neuroblastoma patients as it is toxic to bone marrow, which is already depleted in neuroblastoma patients.

The new treatment uses a compound called ¹⁷⁷Lutetium-DOTATATE, or LuDO for short, which attaches to a different receptor that many neuroblastoma cells have on their surface. It is hoped that LuDO will be as effective in killing neuroblastoma cells as ¹³¹I-mIBG, but have fewer and less severe side effects. It is possible that it will be offered in combination with other radiotherapy drugs in the future.

“This pilot study, offers new hope for the families of children affected by the disease,” said Dr Gaze. “If the trial proves that the new drug is safe and effective, it may become part of the standard treatment for neuroblastoma patients receiving radiotherapy treatment. It is likely to be offered with other drugs in the future – combining drugs is likely to be more effective as more cells will be killed.”

Notes:

For more information, contact Alison Moy, Chief Executive of the Neuroblastoma Alliance UK, on 020 8203 0100, 07580 964 709 or alison@nballiance.org.uk; or Ingrid Marson on 01707 328 511 or ingrid@acornpr.org.uk

The clinical trial has been approved by National Cancer Research Institute, Clinical and Translational Radiotherapy Research Working Group (CTRad) and Clinical Trials Advisory Committee (CTAC), although it is still awaiting approval from the Ethics Committee, Medicines and Healthcare products Regulatory Agency and Administration of Radioactive Substances Advisory Committee (ARSAC).

The pilot was funded by the JACK appeal of the Neuroblastoma Alliance. The JACK appeal was set up by Yvonne and Richard Brown to raise money for their son Jack’s neuroblastoma treatment. Jack sadly died in May 2009.

More information on the pilot study are available in: J. E. Gains, J. B. Bomanji, N. L. Fersht, T. Sullivan, D. D’Souza, K. P. Sullivan, M. Aldridge, W. Waddington, M. N. Gaze. 177Lu-DOTATATE Molecular Radiotherapy for Childhood Neuroblastoma. Journal of Nuclear Medicine, 2011; DOI: 10.2967/jnumed.110.085100

The Neuroblastoma Alliance UK works to help children and families affected by neuroblastoma through providing financial assistance for treatment and to fund leading clinical research in recognised cancer centres.

The Neuroblastoma Children’s Cancer Alliance is a registered charity (no. 1135601), based at 3-4 Sentinel Square, Brent Street, London, NW4 2EL.

Editor’s note on this note-worthy conversation: Mooki Salzman is a mother of a child diagnosed with stage 4 neuroblastoma. Mooki’s brother, Dr Yoram Unguru, is a pediatric oncologist and happens to be a leader in the field in bioethics with regard to pediatric oncology research.

They were invited to present on opposite sides of the question:

Are randomized clinical trials ethical for children with cancer? 

Presented by Mooki Salzman, mom to Toby Pannone, at the annual meeting of the American Society of Bioethics and Humanities in Minneapolis, Minnesota on October 14, 2011. Mooki debated the ethics of phase III clinical trials in pediatric cancer research with her brother Dr Yoram Unguru, Attending Physician/Faculty Member, Division of Pediatric Hematology/Oncology at Herman and Walter Samuelson Children’s Hospital at Sinai, and Associate Faculty, Johns Hopkins Berman Institute of Bioethics.  Dr. Unguru argued to defend the ethical use of phase III clinical trials in pediatric oncology clinical research. He serves as an ethics committee and IRB member and is a member of the Children’s Oncology Group, Committee on Bioethics, and the American Academy of Pediatrics section on Bioethics.

Mooki extends special thanks to her brother Dr Yoram Unguru, Donna Ludwinski, Carie Carter, Pat Lacey and most of all to John London, who started it all with his heartwrenching words and compelling argument.

Who Shall Live and Who Shall Die?

It’s a provocative question, one with Old Testament roots and an attendant seriousness. It’s a question with wide application in ethical discourse.

And although it may be uncomfortable and perhaps sensationalistic, it is a question that we cannot ignore. Certainly in the world of pediatric cancer, “who shall live and who shall die” has very real meaning. For me, since my son Toby was diagnosed with stage IV neuroblastoma, the question “who shall live and who shall die” has become a constant backdrop to daily life.

Neuroblastoma is the most common solid tumor cancer in infants. The median age at diagnosis is 2 years old. At diagnosis, more than half of neuroblastoma patients have disease that has already metastasized to other parts of the body. Children with high-risk disease undergo aggressive high-dose chemotherapy, radiation, surgery, stem cell transplant, differentiation therapy, and antibody therapy. Even after this intense treatment, only 30% survive. If a patient relapses or stops responding to therapy, neuroblastoma is usually viewed as a terminal illness with less than a 10% chance of survival. For those that do survive, the late effects are significant: hearing loss, neurocognitive problems, sterility and secondary cancers.

Since my son was diagnosed in 2007 I have watched helplessly as child after child has died an often agonizing and prolonged death. Neuroblastoma parents describe the death of their children like this: “I’m literally seeing disease erupt all over his body, extraordinarily painful bone mets, fractured bones from disease, organ failure, breathing difficulty, seizures, paralysis, blindness.“ These families face the unthinkable.

In the blink of an eye, we have said goodbye to Liam and Evan, to Lucas, Penelope, Max, Erik, Sam, Erin and so many others that I could burn through my allotted time by reading their names. I think about these children every day. I try not to question their deaths, out of fear that I won’t be able to find my way back to sanity. So instead I remember their vibrancy, their beauty, their quintessential child-ness.

But in the dark hours, I ask why did Liam die? Why does Toby live? It is a terrible question. The randomness howls. And the world spins madly on.

*****

In March 2009, the Children’s Oncology Group released a statement halting the phase 3 trial of ANBL0032, a randomized study of chimeric antibody 14.18 in high risk neuroblastoma. Preliminary results of the phase 3 trial showed a significant increase in survival among those patients who received the antibody, as compared with those who didn’t. Not only was the trial stopped prematurely, but COG also stated that ch14.18 immunotherapy should become a standard part of upfront nb treatment.

The neuroblastoma world is not used to hearing good news. As a reminder, children diagnosed with high-risk disease have a 2 in 3 chance of DYING. So a trial that shows a 20% increase in survival is almost beyond belief.

This is what Dr. John Maris, Chief of the Oncology Division at Children’s Hospital of Philadelphia said about ANBL0032:

“The last clinical trial that showed a new treatment improving outcome in neuroblastoma was published in 1999, which means the study ended in about 1996. That was the one that showed that transplant helped and that Accutane helped, so it’s been a long time.”

But elation quickly turned to unease, as it became clear that ANBL0032 was a randomized trial that started accruing patients almost 8 years earlier, in October 2001. By the time of its halting, over 200 children had been accrued, ½ randomized to receive the antibody and the other ½ not.

Toby was not part of this trial. As a patient at Memorial Sloan-Kettering he, like every child treated there for the last 20 years, received a mouse-derived antibody as part of upfront treatment.

Before I go any further, I want to point out that I am a believer in research. Research has allowed my child to receive the best available treatment and it is important to understand that most neuroblastoma families gratefully sign their children up for trials, because the prognosis otherwise is so poor. In fact, virtually all children treated for neuroblastoma, both high and low-risk, are enrolled on a clinical trial. The cancer is ruthless and research offers a chance at new agents and therapies. I cannot relay how many times parents confess that they just need to keep their children alive until the next trial opens. String together enough trials and maybe you can buy another year or two for your child.

So back to ANBL0032: I, like many others, found myself asking if it was truly necessary to do a phase 3 randomized trial when the phase 1 and 2 data demonstrated that antibody was substantially better than anything we had seen before in the treatment of high-risk neuroblastoma.

More than 30 preclinical and early phase studies on this antibody were completed before ANBL0032 even started. If children were knowingly randomized to the non-antibody arm that was thought to be inferior, the trial was unethical. And more importantly, lives, children’s lives, were sacrificed.

Listen to John London, whose daughter Penelope was randomized to the non-antibody arm:

“I have to say how unethical it is to have designed a trial where 1) the average age of diagnosis is 2; 2) the survival rate for high risk is around 30%; and 3) the survival rate for relapse is below 10% AND then take a potentially promising agent and DISALLOW 50% of these children to receive it. All in the name of “perfect science”. My daughter was one of the children who was turned away. Would it have saved her? Who knows? But I sure would have liked the chance to see. Can you imagine if one of the scientists/researchers/clinicians/protocol designers for ANBL0032 had a child with high risk NB who was denied a potentially promising agent? Randomized studies in High Risk Stage 4 NB sacrifice too many children in the name of science and it needs to change.” 

Not all trials need to be randomized. Many in the medical community say that randomization is necessary to determine the best treatment and that improved survival in pediatric cancer is due to randomized trials. I would counter that increased survival is due to researchers using strong early phase evidence in choosing new treatment to test against old treatment. They are really good at this. Furthermore, if randomization provides better outcomes, why have changes to induction, radiation therapy and use of growth factors NOT been tested in RCTs? And if RCTs supposedly provide “proof” that one treatment is better than another, why is Memorial Sloan-Kettering not doing transplants when this was supposedly proven by 3 separate RCTs? And why is COG not doing rapid induction, as recommended by the International Society of Paediatric Oncology in Europe?

Earlier this year, the New York Times published an acclaimed series of articles on clinical trials in the treatment of melanoma. Many clinicians and researchers have said that the science behind the new drugs has eclipsed the old rules, and ethics, of testing them.

Dr. Charles Sawyers, chairman of human oncology at MSK on melanoma: “With these drugs (in development) that have minimal side effects and dramatic response rates, where we understand the biology, I wonder, why do we have to be so rigorous? This could be one of those defining cases that says, “Look, our system has to change.’”

To that point, if the odds of NB are already so abysmal, why not allow a promising agent to be used for all children? A different trial design could have built on previous knowledge. Perhaps results could have been compared historically to other studies. Perhaps children could have been allowed to cross-over. Either way it is clear that children did not need to be sacrificed to show that antibody is an effective treatment.

Dr. Richard Pazdur, director of the cancer drug office at the FDA has said, “new drugs in development, especially for intractable cancers, might require individual evaluation: This is an unprecendented situation that will, hopefully, be increasingly common, and it may require a regulatory flexibility and an open public discussion.”

The blunt truth is that we cannot control whether our child is diagnosed with cancer. WE do not determine when we live and when we die.

BUT we CAN control what treatment we provide. And where we have the opportunity to offer an increased chance at survival, we have the obligation to do so.

A society is defined by how it treats its most powerless and vulnerable members. We cannot turn a blind eye to injustice. As Abraham Joshua Heschel said, “To accept passively an unjust system is to cooperate with that system.” Yes, I say this to you as the parent of a child with cancer, but we are also fellow human beings. I urge you to search inside, locate our common humanity and give ALL our children a chance at life.

.
******

I am able to stand here today in large part thanks to the support and smarts of my brother, who is sitting right there. His care and advocacy during the past 4 years of treatment have been nothing short of incredible.

It’s not often that a brother and sister find themselves on the front lines of a cancer diagnosis, occupying opposite yet congruent sides of what some term the research/care divide. I believe that with Toby’s diagnosis, brother and sister have been able to transcend our respective boundaries. Certainly in the case of ANBL0032, I hope we are on the same side.

Toby has been the beneficiary of the dedication and care of a team of incredible doctors and nurses at multiple institutions. As a parent, I cope with one child who has cancer. Our doctors and NPs cope with the pain of hundreds of children every day. I want to thank them. They have chosen to face death, yet they engage with life. They care enough about our children to embrace hope, and through their work they affirm that people can change.

Thank you for giving me the opportunity to share my thoughts. I am grateful to be here in your company. I would also like to thank Donna Ludwinski, mother to Erik. She is the force behind my words. Her vast knowledge, pinpoint clarity and graceful support to the neuroblastoma community deserve unending recognition.

Thank you.

July 23, 2011 ~ Neuroblastoma Children’s Cancer Alliance (NCCA) Parent Meeting in Central London, UK

An open meeting for parents to meet and discuss NB topics. Donna Ludwinski will present history of frontline NB treatment, relapse therapies, and current research in US and Europe. Other speakers TBD. See meeting poster for details: NB Parent Meeting London 23 July 2011

http://www.childrenscancer.org.uk/

http://j-a-c-k.org/

Travel supported by NCCA and J-A-C-K Foundation

Dr Ruth Ladenstein presents data in Plenary Session on randomized trial comparing BuMel vs CEM for transplant after Rapid COJEC induction

Considering that neuroblastoma accounts for 7% of pediatric cancers, and pediatric cancers comprises only 1% of adult cancers (that is .07% of all cancers, and high-risk NB makes up only half that number), it is really quite remarkable when highlighted presentations at ASCO focus on neuroblastoma.  This is on the heels of the ch14.18 results which was also big news at ASCO in 2009.

The European SIOPEN trial accrued 1,577 high-risk children since 2002.  Only 43% of these children were randomized for transplant regimen. The randomization was stopped after review showed superiority of BuMel (busulfan + melphalan) over CEM (carboplatin + etoposide + melphalan) in survival. Toxicity was greater in CEM arm, although more VOD (veno-occlusive disease) was observed in BuMel arm.

Dr Julie Park presented data as discussant comparing outcomes with the COG CEM transplant regimen. Clearly BuMel is better than CEM after Rapid COJEC induction, but a question remains if this would be true for the COG induction, which is very different (21 day schedule vs 10 day schedule which presents a different toxicity profile, higher cisplatin use in SIOPEN and no carboplatin is used in COG induction).

This treatment is now standard in SIOP, and COG is incorporating BuMel in a pilot trial.

For more information, see “Can New Standard of Care in Neuroblastoma Be Used in the US?” by Medscape.

http://abstract.asco.org/AbstView_102_79897.html

Abstract:

Background: The HR-NBL1 trial of the European SIOP Neuroblastoma Group randomised 2 MAT regimens with the primary aim to demonstrate superiority based on event free survival (EFS).

Methods: At randomisation closure, 1,577 high-risk neuroblastoma patients (944 males) had been included since 2002; with INSS stage 4 disease (1,369 pts) > 1 year, infants (65 pts) and stage II and III (143 pts) of any age with MYCN amplification. Response eligibility criteria prior to randomisation after Rapid COJEC Induction (J Clin Oncol, 2010) ± 2 courses of TVD (Cancer, 2003) included complete bone marrow remission and ≤ 3, but improved, mIBG positive spots. The MAT regimens were BuMel (oral busulfan till 2006, 4x150mg/m² in 4 equal doses, or after 2006 intravenous use according to body weight and melphalan 140mg/m²/day) and CEM (carboplatin ctn. infusion [4xAUC 4.1mg/ml.min/day], etoposide ctn. infusion [4x338mg/m²day or 4x200mg/m²/day*], melphalan [3x70mg/m²/day or 3x60mg/m²/day*. *reduced if GFR<100ml/min/1.73m²]). A minimum of 3x10E6 CD34/kgBW PBSC were requested. VOD prophylaxis included ursadiol, but not prophylactic defibrotide. Local control included surgery and radiotherapy of 21 Gy. A total of 598 patients were randomised (296 BuMel, 302 CEM). The median age at randomisation was 3 years (1-17.2) with a median follow up of 3 years.

Results: At the last analysis, the Peto rule of p<0.001 was met. A significant difference in EFS in favour of BuMel (3-years EFS 49% vs 33%) was observed as well as for overall survival (3-years OS 60% vs 48%, p=0.004). This difference was mainly related to the relapse and progression incidence, which was significantly (p<0.001) lower with BuMel (48% vs 60%). The severe toxicity rate up to day 100 (ICU and toxic deaths) was below 10%, but was significantly higher for CEM (p=0.014). The acute toxic death rate was 3% for BuMel and 5% for CEM (NS). The acute MAT toxicity profile favours the BuMel regimen in spite of a total VOD incidence of 18% (grade 3:5%). Based on these results and following advice from the DMC, the randomisation was closed early.

Conclusions: BuMel was demonstrated to be superior to CEM and hence is recommended as standard treatment.

ASCO meeting to convene this week

June 3 – 7  I will be in Chicago with 30,000 oncologists and oncology-related professionals (and 350 patient advocates) for the American Society of Clinical Oncology (ASCO) annual meeting, easily the largest oncology meeting in the world. Over 4000 abstracts have been accepted and many different types of sessions are presented including Education, Special, Plenary, Oral Abstract, Clinical Science Symposia, Clinical Problems in Oncology, Posters Discussion, and Trials in progress posters. These sessions are described in more detail on the ASCO site:

http://chicago2011.asco.org/AbouttheMeeting/DescriptionsofSessionTypes.aspx

The sessions are grouped into Tracks, which makes planning easier for attendees. My focus will be on pediatric oncology and clinical trial design, along with close attention to promising clinical trial results in adult solid tumors which may signify promising agents in the near future for pediatric solid tumors.

Below is a short list of items of interest, and the full abstract is available by clicking on each title. I will be reporting on the meeting beginning next week.

Abstracts on neuroblastoma

• PARP-1 inhibitor MK-4827 in combination with radiation as a treatment strategy for metastatic neuroblastoma. | 2011 ASCO Annual Meeting Abstracts
• Phase I study of vincristine, irinotecan, and 131I-MIBG for patients with relapsed or refractory neuroblastoma: A New Approach toNeuroblastoma Therapy (NANT) study. | 2011 ASCO Annual Meeting Abstracts
• Toxicity of 131I-MIBG combined with high-dose chemotherapy in children with refractory neuroblastoma. | 2011 ASCO Annual Meeting Abstracts
• Can the well-credentialed neuroblastoma tumor antigen GD2 be exploited for T-cell-based immunotherapy of pediatric sarcomas? | 2011 ASCO Annual Meeting Abstracts
• A novel anti-GD2 monoclonal antibody (mAb), hu14.18K322A, in children with refractory or recurrent neuroblastoma: Early-phase evaluation. | 2011 ASCO Annual Meeting Abstracts
• Dosimetry, toxicity, and response in a phase IIa trial of no-carrier added iobenguane I-131 (nca-MIBG): A New Approach to NeuroblastomaTherapy (NANT) study. | 2011 ASCO Annual Meeting Abstracts
• Allogeneic transplantation for patients with high-risk or refractory neuroblastoma. | 2011 ASCO Annual Meeting Abstracts
• The prognostic value of semi-quantitative 123I mIBG scintigraphy at diagnosis in high-risk neuroblastoma: Validation of the SIOPEN score method. | 2011 ASCO Annual Meeting Abstracts
• Ototoxicity in children with high-risk neuroblastoma: Prevalence, risk factors, and concordance of grading scales—A report from the Children’s Oncology Group (COG). | 2011 ASCO Annual Meeting Abstracts
• Association of GSTP1 hypermethylation with reduced protein expression and its correlation with clinical stage in neuroblastoma. | 2011 ASCO Annual Meeting Abstracts
• Phase I trial of TPI 287 as a single agent and in combination with temozolomide (TMZ) in patients with refractory or recurrent neuroblastoma (NB) or medulloblastoma (MB). | 2011 ASCO Annual Meeting Abstracts
• Busulphan-melphalan as a myeloablative therapy (MAT) for high-risk neuroblastoma: Results from the HR-NBL1/SIOPEN trial. | 2011 ASCO Annual Meeting Abstracts
• Stratification of patients with neuroblastoma for targeted ALK inhibitor therapy. | 2011 ASCO Annual Meeting Abstracts

Abstracts on pediatric solid tumors

• Cell cycle and apoptotic effects of PM00104 in pediatric cell lines and xenographs. | 2011 ASCO Annual Meeting Abstract
• Second malignant tumors in childhood cancer survivors. | 2011 ASCO Annual Meeting Abstracts
• A phase I study of ifosfamide, oxaliplatin, and etoposide (IOE) in pediatric patients with refractory solid tumors. | 2011 ASCO Annual Meeting Abstracts
• Melanoma as a subsequent neoplasm in survivors of childhood cancer: A report from the Childhood Cancer Survivor Study. | 2011 ASCO Annual Meeting Abstracts
• Characterization of novel potent and selective anaplastic lymphoma kinase (ALK) inhibitors. | 2011 ASCO Annual Meeting Abstracts
• A phase I trial of vorinostat and bortezomib in children with refractory or recurrent solid tumors: A Children’s Oncology Group study. | 2011 ASCO Annual Meeting Abstracts
• A comparison of safety and efficacy of cytotoxic versus molecularly targeted drugs in pediatric phase I solid tumor oncology trials. | 2011 ASCO Annual Meeting Abstracts
• Changes in incidence of infant cancer: Analysis of SEER data 1992-2007. | 2011 ASCO Annual Meeting Abstracts
• Randomized double-blind controlled trial (RCT) of pegfilgrastim as prophylactic therapy in pediatric patients with solid tumors during myelosuppressive chemotherapy. | 2011 ASCO Annual Meeting Abstracts
• Phase I study of pazopanib in children with relapsed or refractory solid tumors (ADVL0815): A Children’s Oncology Group Phase I Consortium Trial. | 2011 ASCO Annual Meeting Abstracts
• Phase I study of bevacizumab, sorafenib, and low-dose cyclophosphamide (CYC) in children and young adults with refractory solid tumors. | 2011 ASCO Annual Meeting Abstracts
• A phase I trial of the histone deacetylase inhibitor panobinostat (LBH589) and epirubicin in patients with solid tumor malignancies. | 2011 ASCO Annual Meeting Abstracts
• A phase I study of temsirolimus and valproic acid for refractory solid tumors in children. | 2011 ASCO Annual Meeting Abstracts
• Feasibility and pharmacokinetic study of potential ABCG2 inihibitor, gefitinib (GB), in combination with irinotecan (IRN) for adolescents and young adults (AYA). | 2011 ASCO Annual Meeting Abstracts
• Phase I study of bevacizumab, sorafenib, and low-dose cyclophosphamide (CYC) in children and young adults with refractory solid tumors. | 2011 ASCO Annual Meeting Abstracts
• A phase I trial of IMC-A12 and temsirolimus in children with refractory solid tumors: A Children’s Oncology Group Study. | 2011 ASCO Annual Meeting Abstracts

Children’s Neuroblastoma Cancer Foundation (CNCF) plans 9th annual medical conference for parents

During the past decade, CNCF has succeeded in bringing an ambitious idea to life. Inviting NB experts to Chicago to speak, providing lodging, meals, some travel funds, and activities for children for NB families who could not otherwise afford to attend such a meeting is a remarkable accomplishment. No other foundation has attempted to duplicate this effort for any other rare disease to our knowledge. Funding such a conference is difficult because most donors understandably want to support research, not education for parents. Because of this conference, many hundreds of parents have been able to meet each other, and hear two days of presentations by various medical experts and engage with them about the disease that afflicts their child. This creates an unprecedented opportunity for parents with children with a deadly disease to learn what they need to know. Special sessions are even provided for grieving families who have lost children to NB.

This all obviously comes with a big price tag, however. Grants to fund such educational activities are very difficult to secure, and the support of NB families who have benefited from this conference in the past is needed now more than ever.

To register and learn more about the conference see:

http://www.cncfhope.org/CNCF_Parent_Education_Conference

Neuroblastoma researchers from around the country are developing new treatments and therapies to improve survival rates and reduce the long-term effects of treatment. Meet some of them at the Children’s Neuroblastoma Cancer Foundation’s 9^th annual Parent Education and Medical Conference:

July 29 & 30th

Hyatt Regency Woodfield-Schaumburg

1800 E. Golf Rd.

Schaumburg, Illinois

Neuroblastoma families have many, many questions, and resources aren’t always readily available. The Parent Education and Medical Conference is a chance for them to get the answers that they seek. Attendees will be able to hear directly from the top neuroblastoma researchers, form valuable networks with other families, and learn how they can become involved in – or create their own – fundraising opportunities in their communities.

Each year, families rave that the conference provides them with a chance to get away, relax, and commiserate with other people who can relate to their circumstance. Children ages 12 and younger can enjoy activities in our “Kids’ Room” * while their parents attend the meetings. (Older children and those not participating in the Kids’ Room are the responsibility of the parents).

The conference can accommodate no more than 200 attendees, and space fills up fast. Breakfast and lunch will be provided. CNCF has reserved 50 hotel rooms for a two-night stay. Complimentary rooms will be available for families that qualify. For information, call CNCF at 866-671-2623.

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