Penetrating the Stroma: Plerixafor Inhibits Chemokine Ligand 12 (of CXCR4) Allowing for Enhanced Biological Therapy in Adenocarcinoma of the Pancreas
The physical size of the structural aspect of pancreatic adenocarcinoma
can be misleading as perhaps 90% of the tumor bulk is actually the
somewhat inert – and not completely understood – stromal tissue that the
“surrounds” the malignant aspect of pancreatic cancer. One practical
effect of the stromal tissue is that it may physically, through
mediating immunosuppression, and otherwise tend to block the effects of
standard treatment modalities – including immunotherapy.
Researcher Fearon and colleagues from Cambridge University UK recently
published findings in the December 10, 2013 issue of the Proceedings of
the National Academy of Sciences of the United States of America
detailing their work in attempting to account for and defeat the effects
of the tumor-protective stromal tissue utilizing a mouse model in the
experimental treatment of pancreatic cancer.
The authors employed the immune-stimulant drug-agent plerixafor (also
known as AMD3100) that is in use in the U.S. for such matters as stem
cell transplantation, and the treatment of AIDS (past usage), lymphoma
and multiple myeloma. Typically, the combination of G-CSF and plerixafor
increases stem cell mobilization in peripheral blood. Also, as another
aspect of its mechanisms of action, plerixafor in the immune system is a
partial antagonist of ligand 12 of the alpha chemokine receptor CXCR4
that depletes the stroma-supporting carcinoma-associated fibroblasts
that express fibroblast activation protein.
On administering plerixafor – the researchers were able to determine
that the agent greatly diminished the mouse pancreatic cancer cells and
rapidly increased local T-cell accumulation. Further and importantly,
the authors through this study have given credence to the gate-keeper
aspect that carcinoma-associated fibroblasts may be exerting through
stroma – that tends to defeat standard therapy in pancreatic cancer (and
other adenocarcinomas). By teasing out the mechanism of this process,
the authors are moving us closer to improved treatment options for
This is highly interesting early work that is deserving of
confirmation and more complete explication.
Dale O’Brien, MD
Do Women Respond More Favorably Than Men to the FOLFIRINOX Regimen in Advanced Cancer of the Pancreas ?
We have come across an interesting recent finding from researchers in Austria.
Greil and colleagues from the Paracelsus Medical University in Salzburg, have published the results of their work which will officially come out in the January issue of the International Journal of Oncology. These findings appear to suggest that the female gender may be a predictor of a positive response to the four-drug regimen known as FOLFIRINOX in the treatment of advanced adenocarcinoma of the pancreas.
The researchers undertook a retrospective analysis of 49 patients with unresectable cancer of the pancreas who were treated with FOLFIRINOX. This included 24 females and 25 males. Although the overall median survival duration of women in this study was not found to be significantly different than the men (15 months vs. 12 months) the women’s progression-free survival, response rates and disease control rates were significantly improved over their male counterparts. This was a surprising finding.
The demographics of the females appeared fairly well matched compared that of the males, although the women showed higher levels of CA 19-9, CEA, Ki-67 and mutated p53 cells. Also perhaps significantly, the women demonstrated more stage 3 tumors and many less stage 4 then the men. Finally, the authors point to the increased number of non-metastatic locally advanced tumors in the male patients versus the females (6 vs. 0) with the idea that these may have nullified the advantage conferred by women having a higher response rate.
This is an intriguing result worthy of further inquiry.
Dale O’Brien, MD
Color this finding: curious (and consequently interesting).
Chinese researchers in Shanghai including Yu and colleagues at Fudan University published recent research findings in the December issue of the Journal of Gastrointestinal Surgery, the official periodical of the Society for Surgery of the Alimentary Tract. They reviewed the results of a number of potential serum tumor markers in 212 patients with confirmed adenocarcinoma of the pancreas.
The aim of the work was to establish which marker could be of best use in predicting which patients were found at an early enough stage of pancreatic cancer to be potentially eligible for surgery. The markers under study included alpha-fetoprotein (AFP), carcinoembryonic antigen CEA), CA19-9, CA50, CA125, CA242, and CA724.
Based on past work one would have predicted the superior marker to be CA 19-9. But in fact, CA125 (often elevated in ovarian cancer) proved superior for this specific task. The selected cut-off value was 19/7 U/mL, which gave a respectable Receiver Operating Characteristic (ROC) area of 0.81. (The ROC area of CA 19-9 with a cut-off of 289.4 U/mL was only 0.66).
We are not sure where to go with this result. But a first step would be to substantiate it. One might imagine that perhaps as a part of a panel – this could be useful. It would be interesting to see how CA125 tracks with early and advanced stages of pancreatic cancer.
Dale O’Brien, MD