Page 35 - Read Online

were selected due to known pathway involvement in to Notch signaling, since not all Notch receptors are
SCLC. For example, a dual mTORC1/2 and class I PI3K created equal. Notch receptors are not always redundant
inhibitor VS-5584 was tested in SCLC xenograft models and in some cases their functions are not only independent
and a PDX model established from a SCLC lymph node but opposite. Notch1 and Notch2 have opposite effects on
metastasis, resulting in significant decreases in tumor Akt in NSCLC. [100] In Luminal B breast cancer, Notch1 and
burden, decreased tumor-initiating frequency and marked Notch4 have similar effects on endocrine resistance but
depletion of cancer stem cells. [93] act through completely different sets of downstream genes
and produce different cellular phenotypes [101] (Espinoza
The Notch signaling pathway is of increasing interest in and Miele, unpublished). Notch1, 3, and 4 are oncogenic
SCLC and as with enteropancreatic NETs, Notch signaling in the breast, while Notch2 has been described as a tumor
in the lung is tissue type and cell context dependent. Notch suppressor in breast cancer cell lines. [102] The mechanism
signaling can promote the growth of NSCLC, yet inhibit of these paralog-specific effects is unknown but may
the growth of SCLC. [94,95] The tumor phenotype in SCLC involve non-canonical signals, such as the inhibitory role
may be driven via Notch3 expression, which is decreased of Notch4 on SMAD [103] or the stimulatory role of Notch1
in SCLC compared to non-tumor lung tissue as measured on NF-κB. [104] The oncogenic activity of Notch4 in the
by immunohistochemistry. SCLC may be the result of mouse mammary gland is independent of CSL and is
[96]
deregulated Notch in cell fate decisions that determine therefore completely or at least partially non-canonical. [105]
differentiation towards the epithelial Clara, ciliated and Another explanation for paralog-specific effects may
pulmonary neuroendocrine cell lineages. In mouse be in quantitative signal intensity of the different Notch
[97]
models with allelic series deletion of Notch1, 2 and 3, all ligands. For example, constitutively activating mutations
three Notch receptors were required in an additive manner in Notch1 and Notch2 are equally oncogenic in a subset
to regulate the abundance of neuroendocrine cells in the of triple negative breast cancer (TNBC), [106] despite the
lung, whereas only contribution from Notch2 was required fact that Notch2 has been described as a tumor suppressor
for Clara/ciliated cell development. [98] in TNBC cell lines. [102] Therefore, the absolute number of
NICD molecules available as a result of overproduction
Over the years, many targeted therapies have been or decreased turnover may dictate different phenotypic
developed to modulate the Notch signaling pathway, consequences. Additionally, paralog-specific effects may
including neutralizing antibodies, decoy ligands, blocking also be achieved by selective activation of chromatin
peptides, natural compounds and -secretase inhibitors sites with different affinity for Notch NICDs, epigenetic
(reviewed in ). The Notch 2/3 neutralizing antibody modifications by NICD binding partners that alters binding
[18]
tarextumab, inhibits tumor growth in mice in a variety of site availability, or by a combination of canonical and
epithelial tumors, but also in SCLC xenograft tumors, non-canonical effects that depends on NICD abundance.
[99]
suggesting that Notch2 and/or Notch3 inhibition can In short, the role of paralog-specific effects has been
be therapeutic in the clinical setting. A novel way of poorly characterized in NETs and is an area in need of
exploiting decreased Notch signaling therapeutically is by further study.
targeting Notch ligands that are frequently overexpressed
even in tumors with low or absent canonical Notch NETs - SKIN
signaling. This approach was pioneered in SCLC, which
frequently expresses high levels of DLL3. Because DLL3 Merkel cell carcinoma (MCC) is a rare, aggressive
can function as a Notch inhibitor by retaining Notch cutaneous NET that occurs most frequently in the elderly
receptors in the cytoplasm or by cis-inhibition, a DLL3 and/or the immunosuppressed, although more than 90% of
mAb conjugated with a DNA damaging toxin was used MCC patients have no known immune dysfunction. [107] It is
as a highly effective chemotherapeutic in preclinical PDX seen primarily in light-skinned individuals and has a male
models of SCLC. These experiments resulted in complete, predominance of 2:1. [108] MCC occurs most frequently in
durable responses 5 months post treatment. The naked sun-exposed areas of skin, particularly the head and neck,
mAb had no therapeutic activity, suggesting that DLL3 followed by extremities and then the trunk. In 80% of cases,
inhibition alone is not sufficient for tumor regression in MCC is associated with the Merkel cell polyomavirus
SCLC. In other studies, it has been proposed that, in (MCPyV). [109,110] Infection with MCPyV is not sufficient to
[14]
addition to the primary SCLC progression as a result of induce tumorigenesis [111] and additional events including
TP53 and RB1 alterations, secondary transitions from non- loss of cellular immune surveillance are required for
small cell lung carcinoma to SCLC can occur following oncogenic transformation. The MCPyV large T-antigen
chemotherapy. This implies phenotypic plasticity from is oncogenic in MCC by binding the retinoblastoma
an epithelial to a neuroendocrine lineage can occur under protein and promoting cell cycle progression. [112] The
treatment-imposed selection. A recent publication by small T-antigen of MCPyV acts downstream of the mTOR
Meder et al. demonstrates that this process is mediated signaling pathway by maintaining hyperphosphorylation
[13]
by the Notch-ASCL1-RB-P53 signaling axis. of 4E-binding protein (4EBP1), resulting in dysregulated
cap-dependent translation in MCC. [113] Patients with
Paralog-specific effects add yet another layer of complexity MCPyV negative MCC tumors have increased DNA
284
Journal of Cancer Metastasis and Treatment ¦ Volume 2 ¦ August 17, 2016 ¦