Page 305 - Read Online

Page 10 of 18 Qureshy et al. J Cancer Metastasis Treat 2020;6:27 I http://dx.doi.org/10.20517/2394-4722.2020.58

cancers is ongoing (NCT02277093) [131] . Pacritinib was also studied in combination with erlotinib in a Phase
I/II trial in NSCLC, which was terminated (NCT02342353).

WP1066
WP1066 inhibits JAK2 phosphorylation and causes JAK2 degradation; it is an analog of the JAK2 inhibitor
AG490, an agent which was widely tested in preclinical modes of solid tumors [132,133] . Preclinical studies
have shown that WP1066 exhibits anti-cancer activity including inhibition of cell proliferation and survival,
and/or inhibition of tumor growth in solid tumors including, but not limited to, bladder cancer, renal cell
carcinoma (in which it was shown to inhibit angiogenesis), HNC, GBM, and NSCLC [134-139] . This agent also
inhibited migration and invasion in bladder cancer, hepatocellular carcinoma, and GBM cell lines [134,139,140] .
WP1066 treatment overcame STAT3-mediated cisplatin resistance in oral squamous cell carcinoma and
ovarian cancer cell lines, and doxorubicin resistance in breast cancer cell lines [141-143] . Two current Phase I
trials investigating the safety and efficacy of WP1066 are being conducted in pediatric medulloblastomas
(NCT04334863) and adult malignant gliomas or brain metastases (NCT01904123).

JAK inhibitors with preclinical evidence supporting activity against solid tumors
While several JAK inhibitors have not yet been tested in patients with solid tumors, they have shown
promising anti-cancer effects in preclinical models. Agents such as AG490, the compound from which
WP1066 was derived, and JAK inhibitor I have been widely tested in preclinical in vitro and in vivo models.
AG490 inhibited STAT3 activation and exhibited anti-cancer effects such as inhibition of cell growth and
[48]
[4]
induction of apoptosis via targeting of JAK2 in preclinical models of breast cancer , gastric cancer ,
pancreatic cancer [144] , and gallbladder cancer [145] , among others. JAK inhibitor I is a JAK1/2/3 inhibitor
that decreased cell proliferation in breast cancer cells [146] , increased apoptosis in esophageal squamous cell
carcinoma cancer stem cells [147] , inhibited STAT3 phosphorylation in HCC cells [148] , and, in combination
with cisplatin, decreased PD-L1 expression in prostate cancer cells [149] . In addition to these agents, there are
a handful of inhibitors that have either already been FDA approved or are being tested currently in clinical
trials for other indications and have also shown promising findings in solid tumor preclinical models. The
following inhibitors, therefore, are potential candidates for clinical testing and use in patients with solid
tumors.

Fedratinib
Fedratinib is an orally bioavailable, small molecule, JAK2 inhibitor that is FDA approved for the treatment
of myelofibrosis [150-153] . NSCLC cells have been shown to be sensitive to fedratinib; sensitivity was shown
to be correlated with elevated JAK2 expression [154] . Two studies showed that fedratinib in combination
with erlotinib (EGFR tyrosine kinase inhibitor) decreased STAT3 activation and increased apoptosis in
erlotinib-resistant NSCLC cells and inhibited tumor growth in in vivo murine models [155,156] . This agent has
also demonstrated cell-killing activity against ovarian and cervical cancer cells [157] . Fedratinib inhibited
mammosphere formation and in combination with carboplatin, inhibited breast cancer tumor growth in
mice [158] . In human papilloma virus (HPV)-positive cervical cancer cells, fedratinib treatment inhibited
JAK2 and STAT3/5 activation, increased apoptosis, and reduced cyclin D1 expression, cell proliferation,
[73]
and colony formation . In HNC cells, treatment with fedratinib increased susceptibility to natural killer
cell killing [159] .

Filgotinib
Filgotinib is a selective JAK1 inhibitor currently being investigated in clinical trials for treatment of
rheumatoid arthritis and inflammatory bowel disease; to date, this drug demonstrates a significant anti-
inflammatory effect, as it reduces levels of cytokines such as IL-6 [160-162] . Findings from preclinical studies
in solid tumors have been reported. The OSM-JAK-STAT pathway has been implicated in progression of
several cancers, including NSCLC; treatment of NSCLC cells with filgotinib resulted in inhibition of STAT3