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August 6, 2019

New Target for Pancreatic Cancer Treatment Shows Potential

JAMA. 2019;322(5):391-392. doi:10.1001/jama.2019.10165

Pancreatic cancer’s poor prognosis can be attributed in part to its treatment resistance due to the dense stroma that surrounds and shields tumor cells. New research in Nature identifies a protein critical for stromal and pancreatic cancer cell communication that when blocked slowed cancer progression and improved treatment efficacy in mouse models of pancreatic cancer.

Anne Weston/EM STP, The Francis Crick Institute/sciencesource.com

Previous work had shown that communication between pancreatic stellate cells—which are typically dormant in normal tissue—and pancreatic cancer cells enhances tumor progression and sustains stellate cell activation, causing the cells to secrete proteins that form a shell around the tumor.

“A massive fibrotic response generating a very dense stroma, medically termed desmoplasia, is pancreatic cancer’s prominent feature accounting for many aspects of its malignancy,” said senior author Tony Hunter, PhD, of the Salk Institute for Biological Studies in La Jolla, California. “Around 8 years ago when we started to conceive the study, the pancreatic stellate cell was emerging as a rising star in the field, and a reciprocal interaction between stellate cells and cancer cells to form a vicious cycle was proposed, but little was known about the detailed mechanisms. We thought the time was ripe to comprehensively investigate the molecular mechanisms underlying the interaction.”

By conducting a systematic investigation of secreted proteins from stellate cells that interact with pancreatic cancer cells, lead author Yu Shi, PhD, and colleagues uncovered an important role for a signaling protein called leukemia inhibitory factor (LIF). LIF is a cytokine involved in embryonic development and was previously identified as a potential anticancer target in glioblastoma based on its role in cancer stem cell biology.

Shi and colleagues found both pharmacological LIF blockade and genetic Lifr gene deletion slowed tumor progression and improved the efficacy of chemotherapy, leading to prolonged survival in mouse models of pancreatic cancer. Targeting LIF is likely to be more successful than simply destroying pancreatic stellate cells because such a strategy worsens tumor progression.

The researchers also found high levels of LIF in tumor tissue and blood from patients with pancreatic cancer. Changes in LIF levels were significantly correlated with tumor progression and chemosensitivity. Therefore, in addition to being a potential target for anticancer therapies, LIF holds promise as a biomarker for both pancreatic cancer and treatment response. Compared with the only FDA-approved biomarker for pancreatic cancer (CA19-9), LIF levels were a better indicator of therapeutic response.

Shi noted that the team was somewhat surprised that their analysis didn’t implicate interleukin 6 (IL-6). “Both LIF and IL-6 belong to the IL-6 cytokine superfamily with similar signal transduction mechanisms, and IL-6 was much more extensively studied and assumed to be important in pancreatic tumorigenesis,” he said. “Although we observed abundant secretion of both cytokines by stellate cells in our initial profiling, our functional screens only highlighted LIF.” Side-by-side comparison between LIF and IL-6 revealed that IL-6 levels are high in mouse pancreatic cancer models but low in human pancreatic cancer samples without significant correlation with pathological parameters, whereas LIF levels are consistently high in both mouse and human pancreatic cancer.

“A key facet of the commanding protumorigenic role assigned to IL-6 in cancer has been its broad direct cancer cell–autonomous actions, together with indirect effects on cancer-associated immune cells, fibroblasts, and adipocytes within the tumor microenvironment. By contrast, other IL-6 family members, including LIF, have been assigned a more restricted function directly on cancer cells in a limited number of cancers,” explained Brendan Jenkins, PhD, who heads the Cancer and Immune Signaling Laboratory at the Hudson Institute of Medical Research in Australia, and was not involved with this study. “With this in mind, the study by Shi et al not only extends the protumorigenic role of LIF to pancreatic cancer, but moreover they uncover a new weapon in the oncogenic armoury of LIF: it can act as a key molecular bridge between the stromal compartment (where it is produced by pancreatic stellate cells) and cancer cells to modulate oncogenic processes.”

Jenkins found it especially encouraging that the anticancer activity of LIF blockade was enhanced when combined with chemotherapy and that anti-LIF therapy increased the chemosensitivity of cancer cells.

“This suggests that LIF also may contribute to the acquired resistance that plagues chemotherapeutic regimens in pancreatic cancer. Collectively, these findings reveal the multifaceted translational potential of LIF, with the promise of implementing anti-LIF therapeutics into the clinic as second-line adjuvant treatment in pancreatic cancer,” Jenkins said.

Shi stressed that the levels of LIF in patient tumors was quite variable, however, for reasons that are not yet understood. “In clinical practice, the therapeutic efficacy of LIF antibody blockade may be maximized by stratifying patients based on LIF levels.”

An open-label phase 1 trial in the United States, Europe, and Canada by Northern Biologics Inc is currently testing a humanized antibody against LIF in patients with relapsed or refractory advanced solid tumors, including pancreatic cancer.

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