Researchers at UCL have developed a new way to deliver drugs that can shut down cancer-promoting mutations in neuroblastoma.
The findings in mice, show the method, which uses tiny bubbles to deliver therapies directly to tumor cells, reduced tumor growth and improved survival.
Neuroblastoma is the most common solid tumor found in children and accounts for about 15% of all cancer-related deaths in children. Tumors develop from certain types of nerve cells and are most commonly found in the abdomen. Children who are diagnosed above the age of one often fail to respond to treatment or relapse at a later time, meaning that there is an urgent need for new treatment options.
The research, published in Advanced Functional Materials and funded by Worldwide Cancer Research, now offers a new potential treatment approach. MYCN is a gene that is associated with poor prognosis and is found to be mutated or overactive in about 20% of neuroblastoma cases.
The gene is usually expressed during fetal development and is involved in cell growth and development. Neuroblastoma cells continue to express too much MYCN, leading to uncontrolled cell growth and division and preventing cancer cells from dying.
Researchers at UCL Great Ormond Street Institute of Child Health have now found a way to silence MYCN by delivering a certain type of genetic material called siRNA, directly to the tumor cells. They developed nanoparticles – or tiny bubbles – that use the leaky blood vessels around the tumor and certain features that are only present on tumor cells to home in on the tumors.
The vast majority of nanoparticles, which were delivered via injection, located to the tumor and successfully shut down the MYCN gene causing the cancer. The treatment caused the tumors to grow at a slower pace and prolonged the time that the mice survived the cancer.
Senior author Professor Stephen Hart, UCL GOS ICH, said: “These findings show that this approach with MYCN siRNA delivered by a nanoparticle is a new potential therapy for neuroblastoma. The next steps would be to develop methods of scaling up production to clinical grade, and to show that the treatment is safe.
Current therapies such as surgery, radio and chemotherapy are effective at removing the primary tumor but, unfortunately, in many cases the tumor will return at other sites in the body, which is much harder to treat. We hope that this therapy might augment conventional therapies and provide a way of targeting the therapy to these new tumor sites.”
Dr. Helen Rippon, chief executive at Worldwide Cancer Research said: “Each year about 100 families in the UK receive the devastating news that their child has developed neuroblastoma. Unfortunately, the cancer is often detected at a relatively late stage and intense treatment is needed.
“We are funding researchers, like Professor Hart, to start new cancer cures and this innovative research shows just how important investment in early-stage discovery research is. Using new methods, such as nanoparticles, to deliver treatment straight to the heart of cancer is an incredibly exciting area of research. These new results now offer hope to patients and their families by paving the way for effective new treatment options.”
The tropomyosin-related kinase receptor (Trk) C is a tyrosine kinase receptor that is preferentially activated by neurotrophin-3 (NT-3) . Other structurally similar members of the neurotrophin receptor family are TrkA, which is the high affinity receptor for nerve growth factor (NGF), and TrkB, which binds brain derived neurotrophic factor (BDNF) and neurotrophin-4/5 . Following the binding of NT-3, TrkC undergoes autophosphorylation and triggers the activation of distinct intracellular signaling pathways, including phosphatidylinositol 3-kinase (PI3K)/Akt, phospholipase C γ and MAP kinase pathways. These pathways are considered to play a key role in mediating the neurotrophin effects on neural cell proliferation, neuronal migration and differentiation, and synaptic organization and plasticity .
Although TrkC is encoded by a single NTRK3 gene, it can be expressed in different isoforms produced through alternative splicing . In addition to the tyrosine kinase containing full-length isoforms (TrkC-FL), TrkC displays a truncated isoform, termed TrkC-T1, which contains the extracellular and transmembrane portions of TrkC-FL, lacks the tyrosine kinase domain, and has a shorter intracellular domain including a unique 83 amino acid sequence . As in the case of the truncated TrkB receptor, TrkC-T1 may negatively modulate the signaling of the TrkC-FL isoform either by sequestering the neurotrophin or forming inactive heterodimers .
Moreover, there is evidence that the binding of NT-3 to TrkC-T1 can signal independently of TrkC-FL to induce membrane ruffling and neuronal apoptosis [4,5,6,7]. NT-3 also binds with high affinity to the common neurotrophin p75NTR receptor , which belongs to the tumor necrosis factor receptor family . p75NTR generally acts as a co-receptor for Trks, increasing their affinity and selectivity for the cognate neurotrophin . However, when overexpressed or present in cells lacking Trks, p75NTR can promote apoptotic cell death [10,11]. Thus, NT-3 has the ability to induce different neurobiological outcomes depending on the predominant activation of a particular receptor molecule.
Besides the crucial role in neurodevelopment, TrkC and the other Trks are known to be important players in affecting the growth and aggressiveness of pediatric tumors of neuronal origin . In neuroblastoma (the most common solid extracranial tumor in children [13,14]) and medulloblastoma the expression of TrkC has been correlated with a good prognosis [15,16,17]. Similarly, enhanced TrkA expression was found to be associated with favorable neuroblastomas which may undergo spontaneous regression .
In neuroblastic primary tumors p75NTR transcript levels have been reported to be positively correlated with increased patient event-free and overall survival . Moreover, p75NTR expression in neuroblastoma cells induces apoptosis . Conversely, in primary neuroblastomas TrkB-FL expression has been found to be associated with MYCN gene amplification, an unfavorable prognostic marker , and its activation by BDNF has been shown to promote neuroblastoma cell survival, resistance to chemotherapy, anoikis and metastasis [22,23,24].
These observations suggest that the identification of pharmacological agents capable of changing the neurotrophin receptor profile of neuroblastoma cells into that of a less malignant phenotype may provide unique tools to counteract the growth of the tumor.
Preclinical studies have provided evidence that histone deacetylase (HDAC) inhibitors display anticancer activity against highly malignant tumors, including neuroblastoma [25,26,27]. In particular, valproic acid (VPA), an antiepileptic and mood stabilizer drug that preferentially inhibits HDAC of class I and IIa [27,28], has been shown to suppress the growth and viability of human neuroblastoma cells both in vitro and in vivo [29,30,31].
We have recently reported that VPA downregulates TrkB expression and signaling and impairs the prosurvival activity of BDNF in human neuroblastoma cells . Moreover, VPA upregulates the expression of the p75NTR/sortilin receptor complex and promotes proNGF-induced neuroblastoma cell death . We also observed that the exposure to VPA enhanced the expression of TrkC , but the mechanisms and the functional outcome of this change were not investigated.
In the present study, we examined the ability of VPA and other HDAC inhibitors to induce TrkC expression in different human neuroblastoma cell lines. Moreover, we investigated the intracellular pathways mediating the TrkC induction and the impact of this change on VPA inhibition of neuroblastoma cell viability.
reference link : https://www.mdpi.com/1422-0067/22/15/7790/htm
More information: Aristides D. Tagalakis et al, Integrin‐Targeted, Short Interfering RNA Nanocomplexes for Neuroblastoma Tumor‐Specific Delivery Achieve MYCN Silencing with Improved Survival, Advanced Functional Materials (2021). DOI: 10.1002/adfm.202104843