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Inhibiting the Effects of the Most Common Mutated Oncogene in Pancreatic Cancer

The K-Ras gene is found to be mutated in 30% of all tumors (human), but this rises to 90% or more in pancreatic cancer (ductal adenocarcinoma of the pancreas). It is considered an “oncogene” meaning a gene whose mutation typically initiates a cascade of proteins that signal for rapid cell growth and division – in this case by promoting an increased binding of the referent protein to GTP (guanosine triphosphate) and a reduced ability to convert GTP to GDP – thus potentiating cell proliferation and ameliorating signals for programmed cell death. As such the K-Ras mutation is one of the most powerful divers of cancer in human beings. And this is assumed to be especially true in pancreatic cancer. Though the K-Ras involvement in pancreatic cancer has been known for decades, direct approaches at altering this mechanism have largely proved elusive.

However, this past June the U.S. National Cancer Institute revealed that it will offer substantive ($10M) grants for scientists to target K-Ras.  Also, a piece of exquisite research by Kevan Shokat and colleagues from the Howard Hughes Medical Institute at the University of California in San Francisco has given impetus to this mission. On November 20, 2013 in the journal Nature these researchers E-published an article on their work detailing their discovery of a specific compound that binds to the K-Ras protein known as G12C which tends to inhibit the effects of the mutated protein.  G12C is the most common mutation of K-Ras whereby cysteine replaces glycine at position 12 of the protein – this mutation is found for example in more than 20,000 patients with lung and colorectal cancer annually in the U.S.

The investigators screened more than five hundred compounds – finally discovering one that binds to a previously unrecognized pocket (identified by crystallographic means) near G12C on the physical structure of the protein. The effect of the binding of this compound to the K-Ras protein appears to reduce the affinity of G12C for GTP, but not for GDP, thus allowing for reinstatement of the more normal (non-mutated) action of K-Ras.

This is a fascinating study that offers future promise for the treatment of pancreatic cancer.

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Dale O’Brien, MD


Lymph Node Surgery for Neuroendocrine Tumors ?

Hawkins and colleagues at Barnes-Jewish Hospital and Washington University School of Medicine in St. Louis, Missouri E-published an article on November 19, 2013 in the journal Annals of Surgery  which examined regional lymph node status and the medical disposition of 136 of their patients who had received surgery for pancreatic neuroendocrine tumors from 1994 through 2012.

In this retrospective study the authors found that lymph node metastases were associated with bigger tumors.  They also found increased regional lymph node presence in those tumors that were found in the head of the pancreas (not in the tail, for instance), those with high Ki-67 levels, and those with lymphatic vascular invasion.  But perhaps the key finding was that at a p < 0.0001 level, the median survival was lower for those patients who evidenced lymph node metastases. The median survival duration for those without these metastases was 14.6 years versus 4.5 years for those with metastases.

The researchers conclude that these data suggest that regional lymphadenectomy may be an important additional step for patients with pancreatic neuroendocrine tumors who undergo pancreatic resection.

This research contains the inherent limitations of retrospective studies in general, and the primary conclusion (that lyphadenectomy may significantly prolong survival) does not necessarily strictly translate.  Nevertheless, it is an interesting finding that may well be true.  Thus, it is deserving of further inquiry  – including perhaps a prospective study.


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Dale O’Brien, MD

Plerixafor Inhibits Chemokine Ligand 12 (of CXCR4): Biological Therapy in Pancreatic Cancer

The physical size of the structural aspect of pancreatic cancer (ductal adenocarcinoma of the pancreas) 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
pancreatic cancer.

This is highly interesting early work that is deserving of confirmation and more complete explication.

More here

Dale O’Brien, MD

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