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Page 12 of 17 Chi et al. J Cancer Metastasis Treat 2020;6:43 I http://dx.doi.org/10.20517/2394-4722.2020.90

is shown to be overexpressed in pancreatic tumor tissues. FAK promotes metastasis by regulating focal
adhesions, matrix metalloproteinase surface expressions and enhancing tumor growth by promoting anti-
apoptotic functions. The combination of FAK inhibitors together with gemcitabine and nab-paclitaxel has
[90]
been shown to delay tumor growth in patient derived xenograph models, relative to chemotherapy alone .
Currently, a phase I clinical trial with FAK inhibitor PF00562271 is under investigation in patients with
advanced pancreatic cancer (NCT00666926).

Connective tissue growth factor inhibitors
CTGF is a protein is highly expressed in PDAC that contributes to the dense desmoplasia. It is also thought
[91]
to protect the cells from hypoxia-mediated apoptosis and drive more aggressive tumor cells selection .
In preclinical study with mouse model of PDAC, pamrevlumab, a monoclonal antibody against CTGF in
[92]
combination with gemcitabine has been shown to prolonged survival . A phase I/II trial involving patients
with unresectable PDAC with pamrevlumab and gemcitabine/nab-paclitaxel (NCT02210559) showed
higher resection rate in the arm with patients who received pamrevlumab. Currently, FDA granted fast
[93]
track designation to pamrevlumab for the treatment of unresectable locally advanced PDAC . A phase III
trial with this agent is recruiting (NCT03941093).

EXPERT OPINION
Surgery, chemotherapy and radiation therapy are three of the most commonly used modalities to treat
pancreatic cancer. However, even with intense chemotherapy regimens, such as FOLFIRINOX, outcomes
for these patients remains dismal with conventional therapies. Cancer cells prevent immune cells from
recognizing them as a threat, thereby, allowing cancer cells to evade the immune system resulting in
continued growth and metastasis. Immunotherapy restores the ability of the immune system to detect
and destroy cancer cells by overcoming mechanisms by which tumors evade and suppress the immune
response.

Recent negative findings from studies evaluating immune checkpoint inhibitors, whether alone or in
combination, have suggested that they may not solely be ideal agents for treatment of pancreatic cancer.
Instead, additional agents that prime the immune microenvironment may be needed to see efficacy. This
may be attributed to the fact that immune checkpoint inhibitor combination therapy has shown efficacy
for immunogenic, “hot” tumors, such as melanoma and lung cancer, while pancreatic cancer on the other
hand, is not an immunogenic tumor, commonly called a “cold” tumor.

It is now known that pancreatic cancer does not contain a lot of immune cells and actually also has
immunosuppressive signals. Therefore, we may have to adopt a “multi-pronged approach”. Such an
approach may include different types of agents, including oncolytic viruses, or vaccines that can prime the
immune microenvironment so that the checkpoint inhibitors can then impart their efficacy. Investigators
have reported feasibility and clinical activity of T-cell therapy in patients with pancreatic cancer. The
question is how do we facilitate bringing in these immune cells?

Pancreatic cancer tumors are well known for the presence of dense desmoplastic stroma that is made
up of pancreatic stellate cells, fibroblasts, immune cells, and extracellular matrix proteins. The tumor
microenvironment is immunosuppressive and dominated by myeloid-derived suppressor cells and
regulatory T cells. Though recent data has shown disappointing results with agents that promised to deplete
the stroma, such as agents that inhibit the sonic Hedgehog signaling pathway and pegylated hyaluronic
acid, it is important to note that the tumor microenvironment does play a significant role in modulating the
immune recognition of PDAC. It is now postulated that extracellular matrix depletion may actually lead to
tumor progression further substantiates a more complex role of desmoplasia in tumor biology.