Pilot project to investigate the impact of adipokines on Acute Lymphoblastic Leukaemia (ALL) outcomes

Obesity is recognised by the World Health Organisation as a global epidemic. Many links have been made between obesity and poorer outcomes for patients diagnosed with a range of diseases, including cancer. In particular, obese children diagnosed with Acute Lymphoblastic Leukaemia (ALL) have a higher chance of relapse, the reasons for which are not yet fully understood. We propose to investigate this phenomenon at the level of the cell, in order to strip back the complexity and understand how the cell’s basic response to chemotherapy is influenced by the increased proportion of fat tissue present in obese patients. We will identify the key molecules secreted by fat tissue in patient samples, and monitor how their levels change before and after the initial phase of chemotherapy. We will then use this information to simulate the conditions found in ALL patients using a cell culture-based system, allowing us to directly measure if these secretions are able to influence the sensitivity of ALL cells to treatment. In this way, we can identify which secretions from fat tissue are able to interfere with chemotherapy, and so design new strategies to overcome this to improve the prognosis of obese childhood ALL patients in the future.

 

Investigating the potential role of CHD1L, a chromatin-remodelling factor involved in the DNA damage response, in childhood neuroblastoma

Neuroblastoma is a very serious cancer, comprising around one tenth of childhood tumours, with around 15 cases in 100 being incurable. Neuroblastoma is unusual as depending on the age of patient diagnosis, cure rates differ greatly due to huge differences in tumour biology. In particular, if children are diagnosed at ages beyond 12 months, the tumour will likely to have spread to other organs, meaning that the disease is likely to resist treatment. The differences between tumours is due to tumours losing large parts, or copying unwanted extra parts, of their DNA by mistake. This causes cells to incorrectly function and become cancerous. Extra copies of one DNA portion, 1q, is found in over one fifth of neuroblastoma patients, associated with poor recovery. We predict that one particular gene (CHD1L) from this 1q DNA region becomes more active in patients with extra 1q DNA, as there are more copies of it. We will measure how much CHD1L is produced in different neuroblastoma cells, to see if in fact more CHD1L is active in cells with extra 1q DNA. This may help lead to simpler diagnostic tests for neuroblastoma patients and to help find the best form of cancer treatment.

 

Understanding the complexity of miRNA-regulated pathways in medulloblastoma

Medulloblastoma (MB) is the most common malignant brain tumour in children. More than one third of children with MB do not survive and essentially 100% of survivors face high risk of recurrence and significant long-term quality of life issues.  Thus, there is a critical need for more effective therapies to combat this disease, particularly for those tumours featuring excessive levels of Myc protein, which triggers uncontrolled cell growth. Since 2009, we have appreciated that microRNAs (miRNAs), small molecules of RNA that regulate how messenger RNAs (mRNA) lead to protein expression, are altered in MB and contribute to its development. This proposal brings together two strands of science – Myc signalling and miRNA biology – to get a better perspective of their role in the biology of MB. Integrated genomic analysis will provide new insights into how miRNAs control gene expression in MB and, in turn, how the Myc oncoprotein, and its inhibitory partner Miz1, repress the expression of some miRNAs to shape the aggressive behaviour of MB. It is hoped that improving our molecular understanding of MB will lead to more targeted therapeutic approaches and identification of disease-specific molecular markers, promoting longer survival in those children diagnosed with aggressive tumours.

 

Development of new drug-resistant cancer cell lines for evaluation of new cancer treatments

Acquired resistance to various anticancer is a major problem in the treatment of children’s cancer in particular high-risk neuroblastoma. The development of chemotherapy drug-resistant cancer cell lines is a long established technique for the study of mechanisms of resistance to chemotherapy and the discovery of new drugs that can potentially overcome this problem. The challenge is to produce resistant cell lines that truly represent the heterogeneous nature of of clinical resistance seen in the patients. Another issue is that most work on development of resistant cancer cell lines has been done using adult derived cancer cells. Kidscan is currently producing a range of resistance cell lines derived from children’s cancers.

 

Target acute leukemia cells in hypoxic bone marrow microenvironment by suppressing mitochondrial metabolic remodelling

In childhood acute lymphoblastic leukemia (ALL), residual leukemic cells persisting in the bone marrow after the first 4 weeks of therapy are termed as minimal residual disease (MRD). These cells are presumed to resistant to the therapy, but why these cells survive while the rest die remains unclear. The bone marrow microenvironment has low oxygen levels (hypoxia). We have recently shown that bone marrow microenvironment induce mitochondrial redox adaptation and confer multidrug resistance to ALL cells. Targeting this redox adaptation process could restore chemosensitivity in drug resistant cells. In on-going experiments, we found that bone marrow microenvironment help ALL cells respond to hypoxia stress and evolve a stress resistant phenotype. Surviving cells, i.e MRD cells, adapt to the stress by reducing energy requirements and increasing the levels of survival (anti-apoptotic) proteins and antioxidants. This stress adaptation also protected against stress induced by chemotherapy, partially through AMPK/Foxo3a/MnSOD2 signalling pathways. Drugs such as Metformin (used in type II diabetes) and Bay 87-2443, which target the mitochondrial respiratory function and cellular hypoxic response, overcome metabolic adaptation and restore chemosensitivity. Thus targeting metabolic adaptation in ALL may lead to the development of new therapeutic strategies for chemoresistance and relapse in childhood ALL.

 

Development of cancer stem cell assays for evaluation of new therapeutic drugs

Cancer stem cell theory suggests that conventional chemotherapy kills the majority of cancer cells but leaves the rare stem cells alive. These stem cells ultimately reseed the tumour, which results in the cancer returning within the patient.  If the theory is correct then it should be possible to treat cancers by only targeting cancer stem cells.  Rather than attacking all of the tumour cells at once, as is the case for traditional cancer therapy. This should result in the tumour slowly shrinking, since the stem cells will no longer be present to replenish cells that naturally die within the cancer.  Cancer stem cell theory has been controversial, however much evidence now exists that supports their existence. Kidscan is currently developing cancer stem cell assays that will allow direct screening of drug activity against this population of cells within a cancer

 

Development of an assay to revolutionise childhood leukaemia research and diagnosis using ground-breaking sequencing technologies

The development of ground-breaking technologies to facilitate the introduction of a new era of whole genome sequencing will revolutionise childhood leukaemia research and diagnosis. Whole genome sequencing has identified many genomic abnormalities of clinical relevance in childhood leukaemia and cancers. Detection of these abnormalities is often difficult due to their complexity and highly inconsistent nature. As some of these abnormalities identify patients who are refractory to conventional chemotherapy, but show response to novel targeted therapies, or have a unique clinical outcome, their accurate detection is vital to guide the most appropriate therapy. Furthermore, ~10% of the human genome is unchartered due to its complex and repetitive DNA sequence, in which novel abnormalities of clinical relevance may reside. A new era of genomic sequencing has begun in which testing for all genomic abnormalities of clinical relevance can be performed in one simple test and unchartered regions of the genome can be explored for the first time. Here we will develop a specific technology imperative to the success of this new generation sequencing, which will improve our understanding of cancer development and identify patients that may benefit from modified treatment to improve their survival.

 

Complex sugars as a novel treatment for children’s cancers

A series of complex sugars or polysaccharides isolated from natural products have been shown to kill cancer cells and has been patented. Structural characterisation of these sugars, determination of their mechanism of action and their preclinical development is continuing.

 

Effects of new sugar based cancer drugs on families of lymphocytes

Previous research, as described in the previous project, has identified existing anticancer properties of complex sugars from shellfish termed ‘glycosaminoglycans’ (GAGs). It is not known if they are effective just on leukaemia cells or if they also target any rapidly dividing cells (e.g. WBC during an infection). Kidscan is funding a study that will culture lymphocytes from healthy bloods to test what effects complex polysaccharides have on them; (toxic cell death, growth promotion, or activation). Various families of lymphocytes will be assessed: T- helper (CD4), T- effector (CD8) and regulatory (Treg) cells. Using a range of cellular assays this study will further understanding of how feasible it may be to develop GAGs for treating childhood cancer.

 

Combining EZH2 inhibition and Radiotherapy for the Treatment of Childhood Rhabdomyosarcomas

Every year over 60 children and teenagers in the UK are diagnosed with rhabdoymosarcoma (RMS), yet treatment regimes and survival rates have remained largely unchanged for decades. Radiotherapy is an important component of treatment for RMS. However, disease recurring at radiotherapy sites and long-term side effects following radiation are common problems. Treatment strategies that increase sensitivity to radiotherapy at the tumour site could reduce recurrences or allow lower doses of radiation to be given.  This offers great promise of increasing patient survival and reducing harmful side effects. We have previously shown that a protein called EZH2 is present at higher levels in RMS than normal tissues and that by decreasing EZH2 in tumour cells we can reduce their growth. As radiotherapy kills cells by damaging DNA and EZH2 is linked to the cells’ ability to repair damage to DNA, we will test the hypothesis that reducing EZH2 activity will enhance the response of RMS cells to radiation.  In parallel, we will test a marker of response to this combination treatment. This pilot study may provide rationale for further preclinical testing. As drugs against EZH2 are currently undergoing clinical trials for other cancers, this combination could be readily introduced for RMS.

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