The malfunctioning of protein kinases (PKs) is the hallmark of numerous diseases. A large share of the oncogenes and proto-oncogenes involved in human cancers encode for PKs. The enhanced activities of PKs are also implicated in many non-malignant diseases, such as benign prostate hyperplasia, familial adenomatosis, polyposis, neuro-fibromatosis, psoriasis, vascular smooth cell proliferation associated with atherosclerosis, pulmonary fibrosis, arthritis glomerulonephritis and post-surgical stenosis and restenosis.
PKs are also implicated in inflammatory conditions and in the multiplication of viruses and parasites. PKs may also play a major role in the pathogenesis and development of neurodegenerative disorders.
For a general reference to PKs malfunctioning or deregulation see, for instance, Current Opinion in Chemical Biology 1999, 3:459-465.
Neuroblastoma, a pediatric malignancy of the sympathetic nervous system, is characterized by clinical and biological heterogeneity. Approximately one-half of neuroblastoma patients present with advanced-stage disease, and despite intensive multimodality therapy, including myeloablative regimens, survival for these children is less than 40%. Identification of tumor targets and advances in target-specific therapies with minimal non-specific toxicity are needed for this patient population. The Trk family of receptor tyrosine kinases is critical for neuronal survival and differentiation during the development of the nervous system. The Trk receptors are differentially expressed in human neuroblastoma and likely play a central role in tumorigenesis and/or cell survival. TrkA is highly expressed by neuroblastomas with favorable biological and clinical features, and expression is associated with patient outcome. In contrast, TrkB expression is restricted to a malignant subset of neuroblastomas. Co-expression of TrkB and its ligand, BDNF, in the majority of neuroblastomas, provides a potential autocrine survival pathway in biologically aggressive, high-risk tumors. Additionally, the recent identification of a constitutively active TrkA splice variant (TrkAIII) that is preferentially expressed in advanced-staged tumors highlights the complex role of Trk signaling in neuroblastoma biology and its potential as a therapeutic target.
Neurotrophin signaling through the Trk family of receptor tyrosine kinases (RTKs) plays a critical role in the development, maintenance and function of the nervous system. Activation of these receptors regulates cell survival, proliferation, migration, differentiation, and apoptosis during development. They exert this influence by modulating the responses of neurons to the neurotrophin family of growth factors in a temporally and spatially regulated manner. The neurotrophins nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT3) are the cognate ligands for TrkA (NTRK1), TrkB (NTRK2), and TrkC (NTRK3), respectively.
Neuroblastoma, a common pediatric tumor of the postganglionic sympathetic nervous system, provides an ideal model for the study of Trk signaling and inhibition in cancer. Neuroblastomas are characterized by clinical heterogeneity, from spontaneous regression in infants to relentless progression in older children. The prognosis for these latter patients remains poor, with three-year event-free survival (EFS) probabilities of 30-40% (5-7). Indeed, neuroblastomas can be classified into distinct subsets based on genetic alterations and biologic features (8), and the expression of Trk receptors likely contributes to these distinct behaviors.
Expression of TrkA in neuroblastoma cell lines has been shown to mediate neuronal differentiation, growth arrest and inhibition of angiogenesis in response to NGF. In contrast, unfavorable neuroblastomas frequently express TrkB and its ligand BDNF, which together comprise an autocrine or paracrine survival pathway. These tumors typically have gross segmental chromosomal aberrations including amplification of the MYCN proto-oncogene. The TrkB/BNDF pathway promotes cell survival, protects cells from injury, and blocks chemotherapy-mediated cell death in vitro. Although a number of genes are likely involved in the development and clinical behavior of favorable and unfavorable neuroblastomas, the pattern of Trk gene expression (TrkA versus TrkB) likely plays a role.
Recent literature has also shown that overexpression, activation, amplification and/or mutation of Trk's are associated with many cancers including neuroblastoma (Brodeur, G. M., Nat. Rev. Cancer 2003, 3, 203-216), ovarian cancer (Davidson. B., et al., Clin. Cancer Res. 2003, 9, 2248-2259), breast cancer (Kruettgen et al, Brain Pathology 2006, 16: 304-310), prostate cancer (Dionne et al, Clin. Cancer Res. 1998, 4(8): 1887-1898), pancreatic cancer (Dang et al, Journal of Gastroenterology and Hepatology 2006, 21(5): 850-858), multiple myeloma (Hu et al, Cancer Genetics and Cytogenetics 2007, 178: 1-10), astrocytoma and medulloblastoma (Kruettgen et al, Brain Pathology 2006, 16: 304-310) glioma (Hansen et al, Journal of Neurochemistry 2007, 103: 259-275), melanoma (Truzzi et al, Journal of Investigative Dermatology 2008, 128(8): 2031-2040, thyroid carcinoma (Brzezianska et al, Neuroendocrinology Letters 2007, 28(3), 221-229.), lung adenocarcinoma (Perez-Pinera et al, Molecular and Cellular Biochemistry 2007, 295(1&2), 19-26), large cell neuroendocrine tumors (Marchetti et al, Human Mutation 2008, 29(5), 609-616), and colorectal cancer (Bardelli, A., Science 2003, 300, 949). In preclinical models of cancer, Trk inhibitors are efficacious in both inhibiting tumor growth and stopping tumor metastasis. In particular, non-selective small molecule inhibitors of Trk A, B and C and Trk/Fc chimeras were efficacious in both inhibiting tumor growth and stopping tumor metastasis (Nakagawara, A. (2001) Cancer Letters 169:107-114; Meyer, J. et al. (2007) Leukemia, 1-10; Pierottia, M. A. and Greco A., (2006) Cancer Letters 232:90-98; Eric Adriaenssens, E. et al. Cancer Res (2008) 68:(2) 346-351) (Truzzi et al, Journal of Investigative Dermatology 2008, 128(8): 2031-2040. Therefore, an inhibitor of the Trk family of kinases is expected to have utility in the treatment of cancer.
Various gene rearrangements of the Trk gene have been implicated in human malignancies. For example, the MPRIP-NTRK1 and CD74-NTRK1 gene rearrangements have been implicated in the development of non-small cell lung cancer. Gene rearrangements TPM3-NTRK1, TGF-NTRK1 and TPR-NTRK1 have been implicated in the development of papillary thyroid cancer. The TPM3-NTRK1 gene rearrangement has been implicated in the development of colorectal cancer. NTRK1, NTRK2 or NTRK3 gene rearrangements have also been identified in glioblastoma, AML and secretory breast cancer. In 2013, Vaishnavi et al. reported novel NTRK1 fusions in 3/91 pan-negative patients with lung adenocarcinoma using NGS and FISH (Vaishnavi et al. Nat Med. 2013 November; 19(11):1469-72).