Blog about neuroblastoma research
My WordPress Blog is about neuroblastoma biology and Cancer Bioengineering Group
It is always a pleasure to host undergraduate students during summer months. Two students joined the RCSI Research Summer School (RSS) Programme. Both are working on the NCRC funded project to understand mechanisms that drive neuroblastoma pathogenesis. None of them had a prior lab experience, but nothing is impossible under John’s supervision.
A full concentration on every single step of the research.
My PhD student John Nolan together with other 41 candidates graduated at the RCSI’s 2017 June Conferring ceremony which took place in the College Hall of 123 St. Stephen’s Green.
He continues his research in neuroblastoma as a Postdoctoral researcher on the project funded by the National Children’s Research Centre. I am glad to be able to keep expertise and young talents in our team.
The research is a long-term investment. It is always built up on the work of the predecessors. Keep research running is crucial to make the dreams come true. Dreams for better treatment options and quality of life.
Thank you to everyone involved in raising funds for CMRF!
CMRF Spring Newsletter can be found here – CMRF-Spring Newsletter Final 15.05.17
It is fantastic to see so knowledgeable and enthusiastic young researchers in my research group. This year, the team is multinational with the Irish students mixing with Belgian and Malaysian. All together they are cracking the code of neuroblastoma microenvironment and tumour cells communication through understanding main differences between conventional cancer cell models and tumours.
The big research plan of the entire team consists of more smaller and focused projects to be completed within 10-12 weeks. All projects are unrestricted, they are driven by the intellectual curiosity of these students. This way is full of ups and downs, frustrations and encouragements when techniques do not work or reagents do not come in as expected. Some cancer concepts can also work differently in the given settings. Simple questions are bringing more challenges than expected. But at the end of the road is the best reward – contribution to the conceptual advancement of neuroblastoma microenvironment.
A Research Project Grant funded by National Children’s Research Centre will be starting in April.
The ultimate aim is to identify biomarkers of tumour response to drugs in the blood of children with high-risk neuroblastoma.
Challenge: Treatment regimens for patients with high-risk neuroblastoma involve intensive, multi-modal chemotherapy. Many patients response to initial therapy very well, but has only short-term effects, with most becoming resistant to treatment and developing progressive disease.
The project has two parts which complement each other.
Part 1
Part 2
How does this project contribute to the biomedical community?
This study aims to contribute to the better understanding of the disease mechanisms and scientific knowledge in the area, and in particular how neuroblastoma cells communicate with other cells helping tumour to create a unique microenvironment and protect themselves from chemotherapy pressure. The new data will give insights in biologically active proteins and miRNAs involved in cell-to-cell communication and drug responsiveness.
What are potential benefits of the proposed research to neuroblastoma patients?
This project aims to develop exosomal biomarkers of tumour response to drugs that might be used to help select patients for treatment and identify novel targets for the development of more effective personalised therapy with the anticipated improvement in outcomes. This work will contribute to the more efficient design of re-initiation treatment, sparing patients unnecessary rounds of chemotherapy and ultimately increasing survival. These new circulating markers will benefit children with high-risk neuroblastoma whose tumours are relapsed leading to less harmful and more tailored treatment options and improving their quality of life.
This week Newpark Hotel Kilkenny is hosting the Irish Association for Cancer Research annual meeting 2017. 
This meeting is the biggest event for Irish cancer researchers.
This is the first time in the history of the IACR meetings when an entire plenary session is solely dedicated to challenges and advancements in childhood cancer.
This session will unite Internationally recognised leaders in childhood cancer research. They will speak about what we know about origin and evolution of childhood cancers (Prof. Tariq Enver), how blood biomarkers can help in stratification and treatment of children (Prof. Sue Burchill), what impact Down syndrome has in the white blood cell cancer development and progression (Prof. Irene Roberts), how epigenetic changes affect tumour pathogenesis and future of therapeutics targeting theses changes (Prof Raymond Stallings).
Today, we are celebrating International Childhood Cancer Day to raise awareness and to express support for children and adolescents with cancer, survivors and their families.
Childhood cancer is an umbrella term for a great variety of malignancies which vary by site of disease origin, tissue type, race, sex, and age.
The cause of childhood cancers is believed to be due to faulty genes in embryonic cells that happen before birth and develop later. In contrast to many adult’s cancers, there is no evidence that links lifestyle or environmental risk factors to the development of childhood cancer.
Every 100th patient diagnosed with cancer is a child.
In the last 40 years the survival of children with most types of cancer has radically improved owing to the advances in diagnosis, treatment, and supportive care. Now, more than 80% of children with cancer in the same age gap survive at least 5 years when compared to 50% of children with cancer survived in 1970s-80s.
Childhood cancer is the second most common cause of death among children between the ages of 1 and 14 years after accidents.
Unfortunately, no progress has been made in survival of children with tumours that have the worst prognosis (brain tumours, neuroblastoma and sarcomas, cancers developing in certain age groups and/or located within certain sites in the body), along with acute myeloid leukaemia (blood cancer). Children with a rare brain cancer – diffuse intrinsic pontine glioma survive less than 1 year from diagnosis. Children with soft tissue tumours have 5-year survival rates ranging from 64% (rhabdomyosarcoma) to 72% (Ewing sarcoma).
For majority of children who do survive cancer, the battle is never over. Over 60% of long‐term childhood cancer survivors have a chronic illness as a consequence of the treatment; over 25% have a severe or life‐ threatening illness.
References:
Gatta G, Botta L, Rossi S, Aareleid T, Bielska-Lasota M, Clavel J, et al. Childhood cancer survival in Europe 1999-2007: Results of EUROCARE-5-a population-based study. Lancet Oncol. 2014.
Howlader N, Noone A, Krapcho M, Garshell J, Miller D, Altekruse S, et al. SEER Cancer Statistics Review, 1975-2011. National Cancer Institute.
Lackner H, Benesch M, Schagerl S, Kerbl R, Schwinger W, Urban C. Prospective evaluation of late effects after childhood cancer therapy with a follow-up over 9 years. Eur J Pediatr. 2000.
Ries L a. G, Smith M a., Gurney JG, Linet M, Tamra T, Young JL, et al. Cancer incidence and survival among children and adolescents: United States SEER Program 1975-1995. NIH Pub No 99-4649. 1999;179 pp
Ward E, Desantis C, Robbins A, Kohler B, Jemal A. Childhood and Adolescent Cancer Statistics , 2014. CA: Cancer J Clin. 2014.
This week can be rated for sure as feeling good, excited and accomplished. A UK based charity – Neuroblastoma UK has awarded a small grant to characterise a pre-clinical model of neuroblastoma which is a collaborative project between our lab and Tissue Engineering Research Group at RCSI. This project will study features of neuroblastoma cells growing on collagen-based scaffolds. The NBUK grant will contribute to one of the most expensive parts of the study – characterisation of cell secreting proteins using antibody-based profiling platforms.
Another research was accomplished yesterday – John Nolan had his Voice Viva examination and successfully defended his PhD Thesis. This 3 year PhD project was funded by the National Children’s Research Centre. As his supervisor, I am delighted for him and wish him best of luck in his research career.
This post is dedicated to parents of children with neuroblastoma. Some parents asked about DFMO – a re-purposing drug. In this post, I tried to collect and summarize information available from academic sources.
Q1: What is DFMO?
Difluoromethylornithine (DFMO, Eflornithine) is an anti-protozoan drug. It was originally developed and FDA approved for the treatment of Trypanosoma brucei gambiense encephalitis (“African sleeping sickness”). DFMO permanently binds to ornithine decarboxylase (ODC), an important enzyme in polyamine metabolism, and prevents the natural substrate ornithine from entering the active site.
By inhibiting ODC, DFMO reduces cellular polyamines and inhibits cell growth and proliferation of actively dividing cells, thus making DFMO an attractive candidate for cancer therapy. In neuroblastoma, a positive regulation of all aspects of polyamine metabolism by MYCN was reported (revived by Bassiri 2015, Gamble 2012). So, it is believed that MYCN amplified neuroblastomas would most benefit of the drug.
Q2: How intense is basic science behind DFMO in neuroblastoma?
To find out the intensity of basic science on DFMO in neuroblastoma search for ‘difluoromethylornithine/DFMO/Eflornithine’ and ‘neuroblastoma’ was run in PubMed, a web-based resource with 26 million citations for biomedical literature from MEDLINE, life science journals, and online books. The search returned 23 papers including 3 reviews and 20 primary research reports published from 1980 to present.
In comparison, I did another search for a novel drug Unituxin (dinutuximab) approved by FDA in 2015. It is monoclonal antibody against the glycolipid disialoganglioside GD2, a biomarker specific for neuroblastoma. Search for ‘anti-GD2 antibody’ and ‘neuroblastoma’ returned 181 papers including 25 reviews and 156 primary articles for the same period.
Q3: Is DFMO in cancer clinical trials?
“ClinicalTrials.gov is a Web-based resource that provides patients, their family members, health care professionals, researchers, and the public with easy access to information on publicly and privately supported clinical studies on a wide range of diseases and conditions. The Web site is maintained by the National Library of Medicine (NLM) at the National Institutes of Health (NIH).
Search for ‘difluoromethylornithine/DFMO/Eflornithine’ in ClinicalTrials.gov returned 36 registered trials across different health conditions.Two of these were withdrawn, the breakdown for the rest 34 is as follows: Adenomatous Polyp (1), Anaplastic Astrocytoma/Recurrent Anaplastic Astrocytoma (1), Bladder Cancer (1), Cervical Cancer/Precancerous Condition (1), Colorectal Cancer (3), Esophageal Cancer (1), Familial Adenomatous Polyposis (1), Gastric Cancer/Gastric Intestinal Metaplasia (1), Hirsutism (2), Human African Trypanosomiasis (5), Neuroblastoma (7), Non-melanomatous Skin Cancer/Precancerous/Nonmalignant Condition (4), Post-solid Organ Transplant/Skin Neoplasms (1), Precancerous Condition (1), Prostate Cancer (2), Pseudofolliculitis Barbae (1), Type 1 Diabetes (1) (Fig. 2). To see full details of 34 trials please click at this Table.
All of them have various statuses (Fig. 3) as well as study design. Importantly, 30 out of 34 studies are focused on safety and efficacy of this drug. Vast majority of studies of DFMO in adult cancers/benign conditions are randomized (16/18 or 89%). Randomization in assignment of patients in studied groups (control and new drug/combination) helps minimize researcher’s bias when comparing effect of the new treatment vs current/no treatment. All trials of DFMO in neuroblastoma are not randomized. Instead, studies use a single group assignment.
Three trails have been either completed/terminated and published results are available at ClinicalTrials.gov (NCT01059071, NCT00033371. NCT00118365).
Q4: What about clinical trials of DFMO in neuroblastoma?
Seven clinical trials on DFMO in neuroblastoma are registered with ClinicalTrials.gov (NCT01586260, NCT02395666, NCT01059071, NCT02679144, NCT02139397, NCT02030964, NCT02559778). One of these has been completed and results are available – ‘Safety study for refractory or relapsed neuroblastoma with DFMO alone and in combination with etoposide (NCT01059071)’.
The trial NCT01059071 was a Phase 1 clinical trial. A phase I clinical trial tries to find out whether a new treatment/drug is safe, what its side effects are, the best dose of the new treatment, if the treatment shrinks the cancer.
Twenty one patients were enrolled and eligible for treatment with DFMO and DFMO + etoposide. These patients were assigned into 4 groups of different DFMO doses (Fig. 4). The treatment was in cycles of 21 days. Cycle 1 – DFMO only followed by cycle 2 – combined treatment of DFMO+etoposide (14 days) and DFMO only (the last 7 days).
According to results of the trial: 14 patients did not complete the treatment due to different reasons. It was not clear what stage/cycle they left the trial.
More details on this trial were provided in the corresponding paper ‘A Phase I Trial of DFMO Targeting Polyamine Addiction in Patients with Relapsed/Refractory Neuroblastoma‘ published in PLOS ONE. PLOS ONE is peer-reviewed, open-access online resource reporting scientific studies from all disciplines. .
Q5: How the study was designed?
As mentioned earlier this study used a single group assignment and a design called ‘3+3’. This design is straightforward and safe. Briefly, it means that for a dose (X) of the drug, 6 patients are selected. Of these, 3 receive the dose X and are monitored for a period of time. If no adverse effects are registered in these 3, then another new 3 patients start the same treatment. The effect of the drug is evaluated on the patent’s health condition before-, during – the treatment and after its completion. This approach is often used in vaccine tests and dose escalation methods in Phase I cancer clinical trials. This type of study can answer mainly two questions: 1) whether the tested drug is safe to use and 2) what doses are safe? The main drawbacks of this design are
Q6: What are main findings of the clinical trial NCT01059071?
The overflow of the study is presented in Fig 5 providing additional information on those who did not complete the trial. Out of 14 participants, disease has progressed in 11 patients – it is 52% of the enrolled participants. Authors highlighted that this phase I study was not designed to evaluate anti-tumour efficacy of DFMO. But tumour response and clinical response were monitored during the study.
According to the paper, 21 patients received at least one dose of DFMO only (Cycle 1, 21 days). During this cycle, 3 patients were withdrawn. All of them were assessed for safety of DFMO.
Adverse effects in response to DFMO alone were: anemia – 3, ANC decrease – 2, decreased platelet count – 2, ALT increase – 1, AST increase – 1, anorexia – 1, constipation – 1, diarrhea – 1, infection (conjunctivitis) – 1, hypoalbuminemia – 1, hypophosphatemia – 1, increased GGT – 1, sleep disturbance – 1, urinary retention – 1 and vomiting – 1.
Eighteen of them completed cycle 1 and continued treatment with DFMO+etoposide for another 4 cycles followed with DFMO only therapy for a number of cycles. Their clinical response data were examined for efficacy of DFMO alone.
Three out of 21 participating patients in this clinical trial remain alive and disease free between 2–4.5 years after starting DFMO.
Authors concluded that
DFMO doses of 500-1500mg/m2/day are safe and well tolerated in children with relapsed NB
Research and review papers covering DFMO in neuroblastoma:
