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Molecular Drivers in Lung Adenocarcinoma: Therapeutic Implications
Published in Surinder K. Batra, Moorthy P. Ponnusamy, Gene Regulation and Therapeutics for Cancer, 2021
Imayavaramban Lakshmanan, Apar Kishor Ganti
The anaplastic lymphoma kinase (ALK) gene encodes a tyrosine kinase receptor. The carcinogenic effect of ALK is often seen when it forms a fusion gene with any of several other genes such as, Nucleophosmin (NPM) or Echinoderm microtubule-associated protein-like 4 (EML-4). In addition, increased gene copy number or mutations within the gene can also lead to carcinogenesis. As the name suggests, the pathogenic role of ALK was originally identified in a subset of anaplastic large cell lymphomas with a t(2; 5) (p23; q35) translocation (NPM-ALK).
Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
In healthy individuals the ALK (Anaplastic Lymphoma Kinase) protein is involved in the development and function of nervous system tissue. However, chromosomal translocations and fusions can give rise to an oncogenic form of ALK that has been implicated in the progression of non-small-cell lung carcinoma (NSCLC) and other cancer types. Approximately 4% of patients with NSCLC have a chromosomal rearrangement that generates a fusion gene between EML4 (Echinoderm Microtubule-Associated Protein-Like 4) and ALK, which results in constitutive kinase activity that contributes to carcinogenesis and drives the malignant phenotype. Researchers first identified the ALK fusion gene in 1994 as a chromosomal rearrangement in anaplastic large-cell lymphoma (ALCL). It is now known that 4–7% of NSCLC patients have EML4-ALK translocations, and genetic studies have confirmed that abnormal expression of ALK is a key driver in certain types of NSCLC, neuroblastomas, and ALCL. Interestingly, patients with this gene fusion are typically younger non-smokers who do not have mutations in either the EGFR or the K-RAS genes. Since ALK is not normally expressed significantly in normal adult tissues, it is a rational molecular target for cancer therapy.
Overview of Therapeutic Biomarkers in Cancer
Published in Sherry X. Yang, Janet E. Dancey, Handbook of Therapeutic Biomarkers in Cancer, 2021
Sherry X. Yang, Janet E. Dancey Treatment
Anaplastic lymphoma kinase (ALK) is abundantly expressed and oncogenic in cancers affecting children (anaplastic large cell lymphoma (ALCL) and neuroblastomas) and adults (most commonly non-small cell lung carcinomas (NSCLC) and rarely in other solid tumors), while it is absent from the majority of normal adult tissues. ROS1 is a receptor tyrosine kinase (encoded by the gene ROS1) with structural similarity to the ALK protein. The ALK fusion gene occurs in 3% to 5% of NSCLC, and incidence of ROS1 gene rearrangement is estimated at up to 2% of NSCLC [39, 40]. There are now three generations of inhibitors to these therapeutic targets. Crizotinib, a small-molecule inhibitor of the receptor tyrosine kinases c-Met and ALK, was approved for the treatment of patients with metastatic NSCLC whose tumors harbor ALK or ROS1 gene rearrangement (positivity) in 2011 (Chapter 16). Concurrently with the drug approval, FDA approved its companion diagnostic test—the Vysis ALK Break-Apart FISH Probe Kit (Abbott Molecular, Inc.) [41, 42]. Ceritinib in 2014 and alectinib in 2015 were approved for the treatment of ALK-positive, metastatic NSCLC who have progressed or are intolerant to crizotinib. Additionally, a next-generation ALK/ROS1 tyrosine kinase inhibitor lorlatinib was approved as second-line or third-line therapy. It is a selective brain-penetrant ALK/ROS1 TKI active against the most known resistance mutations.
High grade gliomas in young children: The South Thames Neuro-Oncology unit experience and recent advances in molecular biology and targeted therapies
Published in Pediatric Hematology and Oncology, 2021
Janice Pearce, Komel Khabra, Henry Nanji, Joanna Stone, Karen Powell, Danielle Martin, Bassel Zebian, Samantha Hettige, Zita Reisz, Istvan Bodi, Safa Al-Sarraj, Leslie R. Bridges, Matthew Clarke, Chris Jones, Henry C. Mandeville, Sucheta Vaidya, Lynley V. Marshall, Fernando Carceller
The Anaplastic Lymphoma Kinase (ALK) is a receptor tyrosine kinase involved in cell proliferation, progression and survival.35 Upregulation of ALK signaling can result from chromosomal translocations, activating mutations and gene amplifications.35 ALK has been found overexpressed in adult glioblastomas and ALK fusions have been reported in <1% pediatric HGG.36,37 ALK-fused tumors represent 41–47% of fusion-positive infant gliomas.4,5 ALK inhibitors have shown clinical activity in anecdotal reports of pediatric solid tumors and infant gliomas.4,38,39 Importantly, ALK-fused tumors seem to respond better to ALK inhibition than ALK-mutated tumors.40 Novel ALK inhibitors seem to display enhanced blood-brain barrier penetration.4,5 Overall, these findings make ALK inhibitors a very attractive strategy in ALK-fused infant gliomas.
Pathology and systemic therapy of non-clear cell renal cell carcinoma: an overview
Published in Expert Review of Anticancer Therapy, 2021
Lothar Bergmann, Sarah Weber, Arndt Hartmann, Marit Ahrens
Frequent limitations of these trials are a pooled analysis of multiple distinct entities and/or a lack of comparator. It must be borne in mind that nccRCCs are heterogenous not only in terms of histology, but also in prognosis, as described earlier. As a result, there is still a lack of knowledge with regard to the best treatment strategy in different nccRCC subgroups. To fill this gap, a better understanding of the biological and molecular behaviors of nccRCC is needed, which is only possible if nccRCC is not excluded across-the-board from clinical trials. These tumors should ideally be included in special histology-tailored trials. For example, in view of the frequently found mutations in the TSC/mTOR signaling pathway in NOS-classified oncocytic tumors, trials might seek to demonstrate possible effects of mTOR inhibitors in this entity. Furthermore, treatment with ALK inhibitors might be offered in anaplastic lymphoma kinase (ALK) translocation-associated RCC after failure of other treatments. However, a limitation of this approach may be the small number of patients eligible for those trials. This is a problem also common to other rare and diverse entities, and necessitates the execution of international multicenter rather than single-center trials.
The expression of CD30 and its clinico-pathologic significance in peripheral T-cell lymphomas
Published in Expert Review of Hematology, 2021
Kennosuke Karube, Yoshihide Kakimoto, Yukio Tonozuka, Koichi Ohshima
Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of aggressive non-Hodgkin lymphomas (NHL) arising from mature T-cell and natural killer (NK) cell lineages. The 2017 WHO classification for lymphoid neoplasms lists approximately 30 different PTCL subtypes that are distinguished by phenotypic, morphologic, and genetic characteristics [1,2]. PTCLs account for approximately 10% of all NHL cases in the US and Europe but their relative prevalence is markedly higher in East Asian countries [3,4]. PTCLs have been reported to account for 22% of all NHL cases in South Korea, 25% in Japan, and 33% in China [4]. Given the aggressive clinical course of PTCL, these patients have a poor prognosis. Until recently, initial PTCL treatment has relied upon CHOP (cyclophosphamide, doxorubicin, vinblastine, and prednisone) or CHOP-like chemotherapy regimens [1,5,6]. A study found that patients with the histological PTCL subtype of anaplastic lymphoma kinase (ALK)-positive anaplastic large-cell lymphoma (ALCL) and had an International Prognostic Index (IPI) of 0 or 1 responded relatively well to chemotherapy and enjoyed a 5-year overall survival (OS) rate of 90% [7]. In contrast, ALK-negative ALCL with an IPI of 4 or 5 was associated with a low 5-year OS rate of 13% [7]. For the more common PTCL histological subtypes of PTCL not otherwise specified (NOS) and angioimmunoblastic T-cell lymphoma (AITL), only 32% of patients survive beyond 5 years with conventional chemotherapy and more effective treatment strategies are needed [7].