Targeted molecular therapy for neuroblastoma

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Targeted molecular therapy for neuroblastoma involves treatment aimed at molecular targets that have a unique expression in this form of cancer. Neuroblastoma, the second most common pediatric malignant tumor, often involves treatment through intensive chemotherapy. A number of molecular targets have been identified for the treatment of high-risk forms of this disease. Aiming treatment in this way provides a more selective way to treat the disease, decreasing the risk for toxicities that are associated with the typical treatment regimen. Treatment using these targets can supplement or replace some of the intensive chemotherapy that is used for neuroblastoma. These molecular targets of this disease include GD2, ALK, and CD133. GD2 is a target of immunotherapy, and is the most fully developed of these treatment methods, but is also associated with toxicities. [1] ALK has more recently been discovered, and drugs in development for this target are proving to be successful in neuroblastoma treatment. The role of CD133 in neuroblastoma has also been more recently discovered and is an effective target for treatment of this disease.

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Identifying High-Risk Patients

High-risk cases of neuroblastoma are difficult to treat, even through intensive chemotherapy. For this reason, molecular targets have been identified and are being developed for treatment in patients who have more difficulty responding to treatment. There are a number of genetic factors that can be used to identify high-risk patients. In neuroblastoma cells, there can be amplification of genomic DNA regions, loss of genomic DNA regions, and genetic abnormalities. [2] All of these factors can contribute to an advanced disease state in high-risk patients.

Amplification occurs within a protein called the MYCN oncogene. This protein is amplified in approximately 20% of primary neuroblastoma tumors and is associated with advanced disease state and treatment failure. [2]

Loss of genomic regions by deletion can occur at chromosomes 1p and 11q. Loss at 1p is correlated with MYCN amplification and advanced disease state. [2] The loss at 11q is not related to MYCN, but is correlated with adverse patient outcomes. [2]

Genetic abnormalities frequently occur in a tumor-suppressor gene called caspase 8. Inactivation of this gene will result in tumor cell survival. [2]

Table 1 summarizes the genomic factors used to identify high-risk patients. [1] [2] [3] [4]

Table 1. Genomic Identification of High-Risk Patients
Genomic LocationPrevalence (in primary NB cells)Consequences
Amplification of DNA RegionMYCN oncogene~20%advanced disease state

treatment failure

Loss of DNA Regions1p Chromosome~30-35%MYCN amplification

advanced disease state

11q Chromosome~35-45%adverse patient outcomes
Specific Gene AbnormalityCaspase 8 Gene~25-35%tumor cell survival

Treatment Using Molecular Targets

Anti-GD2 Immunotherapy

GD2 is a glycolipid that is expressed on the surface of neuroblastoma cells. [1] It is targeted through immunotherapy in neuroblastoma treatment using monoclonal antibodies. [1] These monoclonal antibodies are used to block GD2 expression, and are thus referred to as anti-GD2 agents. They can be used for tumor-specific therapy because GD2 expression is weak and limited to certain areas in normal human tissue. [3] Therefore, its expression can be easily targeted in tumor cells. [3] While anti-GD2 antibodies are effective in clearing the remaining tumors in neuroblastoma patients, there have also been major toxicities associated with the use of this form of treatment. These toxicities include neuropathic pain, capillary leak syndrome, and hypersensitivity reaction. [1] Anti-GD2 antibodies have been developed for immunotherapy treatment of neuroblastoma and can be grouped into first-generation and second-generation antibodies. [3]

  1. 14G2a
  2. ch14.18
  3. 3F8
  1. Hu14.18-IL-2
  2. Hu14.18K332A
  3. mAb1A7

All of these antibodies are going through clinical trial processes for the treatment of neuroblastoma. The most extensively studied of these antibodies is ch14.18. [3] Through randomized trials, it has been found that treatment with ch14.18 is most effective when combined with cytokines, such as granulocyte macrophage colony-stimulating factor (GM-CSF) and interleukin-2 (IL-2). [3] This combination therapy improves the outcome of high-risk neuroblastoma, but does not decrease the risk of toxicities. [3] For this reason, the second-generation antibodies have been developed, which have fewer associated toxicities but are continuing trials to determine their therapeutic efficacy. [3]

ALK in Familial Neuroblastoma

Mutations in the anaplastic lymphoma kinase (ALK) oncogene can be inherited and are a major cause of neuroblastoma. [2] These mutations occur in approximately 5-15% of neuroblastoma cases. [2] ALK has recently been discovered as a molecular target of chemotherapy in the treatment of neuroblastoma patients. Drugs that target ALK are referred to as ALK inhibitors. ALK is expressed on the surface of neuroblastoma tumor cells, making it easily accessible as a target for cancer treatment. [1] In neuroblastoma patients who do not possess a mutated form of ALK, targeting the non-mutated form of ALK on a tumor cell can also be beneficial. [1] This will cause the tumor to undergo apoptosis, which is programmed cell death. [1] ALK inhibitors can also be used to treat another cause of neuroblastoma referred to as MYCN gene amplification. [1] Amplification of the MYCN protein is a genetic mutation associated with neuroblastoma tumors. [1] MYCN amplification is correlated with a specific mutation in ALK, referred to as the F1174L mutation. [1] ALK inhibitors can target this mutation and suppress the MYCN protein in the tumor cell. [1]

The following is a list of ALK inhibitors currently in clinical trials for treatment of neuroblastoma: [5]

Crizotinib was the first of these drugs to enter clinical trials and is the sole available ALK inhibitor, approved by the FDA on August 26, 2011. [5] Thus far, it has proven its efficacy in treating adults with non-small-cell lung carcinoma (NSCLC), another form of cancer in which ALK plays a role. [6] The drug is currently in phase III clinical trials to test its use in treating pediatric cancer types, such as neuroblastoma.

CH542802 is currently in phase I/II trials and is being shown to inhibit the growth of neuroblastoma cells with the amplified expression of ALK. [3]

ASP3026 is in phase I trials for ALK-related malignancies. It is currently being tested in adults but also can be a viable treatment for neuroblastoma due to its ALK inhibiting characteristics. [5]

Ceritinib was approved by the FDA in April 2014 for treatment of ALK-positive metastatic non-small cell lung cancer. Like crizotinib, it has proven to be efficacious in adults and is also being tested for its efficacy in pediatric neuroblastoma cells. [3]

AP26113 is a dual inhibitor of ALK and epidermal growth factor receptor. It is going through phase I/II clinical trials for treatment of neuroblastoma and NSCLC. [5]

CD133 Biomarker

CD133 is shown to be a marker of tumor-initiating or cancer stem cells in neuroblastoma. The tumor-initiating properties of CD133 have been discovered through studies such as the one performed by Cournoyer et al. [4] The cells from neuroblastoma patients have been examined, comparing those with a high expression of the CD133 glycoprotein to those with a low expression of CD133. [4] The following are the characteristics of high-expression CD133 that provide evidence for its tumor-initiating properties: [4]

The tumor-initiating properties of CD133 provide evidence for it to be a practical target of chemotherapeutic treatment for neuroblastoma. Through genotype analysis CD133 expression is found to be associated with the expression of the EFNA2 protein. [4] This protein can play a role in cancer development. It is expressed in stem cells and can promote the formation of tumors. [4] For these reasons, it can also be used for chemotherapy treatment in neuroblastoma patients. Through genotype analysis, the presence of this protein can be detected in neuroblastoma patients who also have high-expression CD133. [4] In developing drugs for the treatment of neuroblastoma, pharmaceutical companies are experimenting with the use of CD133 and the associated EFNA2 protein as targets. [4]

Related Research Articles

Retinoblastoma Medical condition

Retinoblastoma (Rb) is a rare form of cancer that rapidly develops from the immature cells of a retina, the light-detecting tissue of the eye. It is the most common primary malignant intraocular cancer in children, and it is almost exclusively found in young children.

Anaplastic large-cell lymphoma Medical condition

Anaplastic large cell lymphoma (ALCL) refers to a group of non-Hodgkin lymphomas in which aberrant T cells proliferate uncontrollably. Considered as a single entity, ALCL is the most common type of peripheral lymphoma and represents ~10% of all peripheral lymphomas in children. The incidence of ALCL is estimated to be 0.25 cases per 100,000 people in the United States of America. There are four distinct types of anaplastic large cell lymphomas that on microscopic examination share certain key histopathological features and tumor marker proteins. However, the four types have very different clinical presentations, gene abnormalities, prognoses, and/or treatments.

Neuroblastoma Medical condition

Neuroblastoma (NB) is a type of cancer that forms in certain types of nerve tissue. It most frequently starts from one of the adrenal glands but can also develop in the neck, chest, abdomen, or spine. Symptoms may include bone pain, a lump in the abdomen, neck, or chest, or a painless bluish lump under the skin.

GD2 Chemical compound

GD2 is a disialoganglioside expressed on tumors of neuroectodermal origin, including human neuroblastoma and melanoma, with highly restricted expression on normal tissues, principally to the cerebellum and peripheral nerves in humans.

Cancer immunotherapy Artificial stimulation of the immune system to treat cancer

Cancer immunotherapy is the artificial stimulation of the immune system to treat cancer, improving on the immune system's natural ability to fight the disease. It is an application of the fundamental research of cancer immunology and a growing subspeciality of oncology.

Targeted therapy

Targeted therapy or molecularly targeted therapy is one of the major modalities of medical treatment (pharmacotherapy) for cancer, others being hormonal therapy and cytotoxic chemotherapy. As a form of molecular medicine, targeted therapy blocks the growth of cancer cells by interfering with specific targeted molecules needed for carcinogenesis and tumor growth, rather than by simply interfering with all rapidly dividing cells. Because most agents for targeted therapy are biopharmaceuticals, the term biologic therapy is sometimes synonymous with targeted therapy when used in the context of cancer therapy. However, the modalities can be combined; antibody-drug conjugates combine biologic and cytotoxic mechanisms into one targeted therapy.

Non-small-cell lung carcinoma Any type of epithelial lung cancer other than small-cell lung carcinoma

Non-small-cell lung carcinoma (NSCLC) is any type of epithelial lung cancer other than small-cell lung carcinoma (SCLC). NSCLC accounts for about 85% of all lung cancers. As a class, NSCLCs are relatively insensitive to chemotherapy, compared to small-cell carcinoma. When possible, they are primarily treated by surgical resection with curative intent, although chemotherapy has been used increasingly both preoperatively and postoperatively.

Anaplastic lymphoma kinase

Anaplastic lymphoma kinase (ALK) also known as ALK tyrosine kinase receptor or CD246 is an enzyme that in humans is encoded by the ALK gene.

Treatment of lung cancer refers to the use of medical therapies, such as surgery, radiation, chemotherapy, immunotherapy, percutaneous ablation, and palliative care, alone or in combination, in an attempt to cure or lessen the adverse impact of malignant neoplasms originating in lung tissue.

Targeted therapy of lung cancer refers to using agents specifically designed to selectively target molecular pathways responsible for, or that substantially drive, the malignant phenotype of lung cancer cells, and as a consequence of this (relative) selectivity, cause fewer toxic effects on normal cells.

Adenocarcinoma of the lung Medical condition

Adenocarcinoma of the lung is the most common type of lung cancer, and like other forms of lung cancer, it is characterized by distinct cellular and molecular features. It is classified as one of several non-small cell lung cancers (NSCLC), to distinguish it from small cell lung cancer which has a different behavior and prognosis. Lung adenocarcinoma is further classified into several subtypes and variants. The signs and symptoms of this specific type of lung cancer are similar to other forms of lung cancer, and patients most commonly complain of persistent cough and shortness of breath.

Crizotinib ALK inhibitor for treatment of non-small-cell lung cancer

Crizotinib, sold under the brand name Xalkori among others, is an anti-cancer medication acting as an ALK and ROS1 inhibitor, approved for treatment of some non-small cell lung carcinoma (NSCLC) in the US and some other countries, and undergoing clinical trials testing its safety and efficacy in anaplastic large cell lymphoma, neuroblastoma, and other advanced solid tumors in both adults and children.

ALK inhibitor

ALK inhibitors are anti-cancer drugs that act on tumours with variations of anaplastic lymphoma kinase (ALK) such as an EML4-ALK translocation. They fall under the category of tyrosine kinase inhibitors, which work by inhibiting proteins involved in the abnormal growth of tumour cells. All the current approved ALK inhibitors function by binding to the ATP pocket of the abnormal ALK protein, blocking its access to energy and deactivating it. A majority of ALK-rearranged NSCLC harbour the EML4-ALK fusion, although as of 2020, over 92 fusion partners have been discovered in ALK+ NSCLC. For each fusion partner, there can be several fusion variants depending on the position the two genes were fused at, and this may have implications on the response of the tumour and prognosis of the patient.

Gene expression profiling has revealed that diffuse large B-cell lymphoma (DLBCL) is composed of at least 3 different sub-groups, each having distinct oncogenic mechanisms that respond to therapies in different ways. Germinal Center B-Cell like (GCB) DLBCLs appear to arise from normal germinal center B cells, while Activated B-cell like (ABC) DLBCLs are thought to arise from postgerminal center B cells that are arrested during plasmacytic differentiation. The differences in gene expression between GCB DLBCL and ABC DLBCL are as vast as the differences between distinct types of leukemia, but these conditions have historically been grouped together and treated as the same disease.

EML4-ALK positive lung cancer Medical condition

EML4-ALK positive lung cancer is a primary malignant lung tumor whose cells contain a characteristic abnormal configuration of DNA wherein the echinoderm microtubule-associated protein-like 4 (EML4) gene is fused to the anaplastic lymphoma kinase (ALK) gene. This abnormal gene fusion leads to the production of a protein (EML4-ALK) that appears, in many cases, to promote and maintain the malignant behavior of the cancer cells.

Molecular oncology is an interdisciplinary medical specialty at the interface of medicinal chemistry and oncology that refers to the investigation of the chemistry of cancer and tumors at the molecular scale. Also the development and application of molecularly targeted therapies.

Inflammatory myofibroblastic tumour Medical condition

Inflammatory myofibroblastic tumor (IMT) is a rare neoplasm of the mesodermal cells that form the connective tissues which support virtually all of the organs and tissues of the body. IMT was formerly termed inflammatory pseudotumor. Currently, however, inflammatory pseudotumor designates a large and heterogeneous group of soft tissue tumors that includes inflammatory myofibroblastic tumor, plasma cell granuloma, xanthomatous pseudotumor, solitary mast cell granuloma, inflammatory fibrosarcoma, pseudosarcomatous myofibroblastic proliferation, myofibroblastoma, inflammatory myofibrohistiocytic proliferation, and other tumors that develop from connective tissue cells. Inflammatory pseudotumour is a generic term applied to various neoplastic and non-neoplastic tissue lesions which share a common microscopic appearance consisting of spindle cells and a prominent presence of the white blood cells that populate chronic or, less commonly, acute inflamed tissues.

Pembrolizumab Pharmaceutical drug used in cancer treatment

Pembrolizumab, sold under the brand name Keytruda, is a humanized antibody used in cancer immunotherapy that treats melanoma, lung cancer, head and neck cancer, Hodgkin lymphoma, stomach cancer, and cervical cancer. It is given by slow injection into a vein.

Atezolizumab

Atezolizumab, sold under the brand name Tecentriq, is a monoclonal antibody medication used to treat urothelial carcinoma, non-small cell lung cancer (NSCLC), triple-negative breast cancer (TNBC), small cell lung cancer (SCLC), and hepatocellular carcinoma (HCC). It is a fully humanized, engineered monoclonal antibody of IgG1 isotype against the protein programmed cell death-ligand 1 (PD-L1).

Entrectinib TKI inhibitor used for cancer treatment

Entrectinib, sold under the brand name Rozlytrek, is an anti-cancer medication used to treat ROS1-positive non-small cell lung cancer and NTRK fusion-positive solid tumors. It is a selective tyrosine kinase inhibitor (TKI), of the tropomyosin receptor kinases (TRK) A, B and C, C-ros oncogene 1 (ROS1) and anaplastic lymphoma kinase (ALK).

References

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  6. ↑ Thiele, Carol J.; Cohn, Susan L. (2012). "Genetically informed therapies- a "gift" for children with cancer". Clin Cancer Res. 18 (10): 2735–2739. doi:10.1158/1078-0432.ccr-11-1940. PMC   3354647 . PMID   22589482 . Retrieved 4 November 2012.[ permanent dead link ]
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