Map of Pancreatica Walks and Runs

DNA Found in Exosomes in Cancer of the Pancreas – with Characteristic Mutations !

We recently commented (here) on the interesting properties of exosomes that were explored as possible messengers within the body including saliva in the context specifically of biomarkers in pancreatic cancer by Wong and dental colleagues at UCLA.

Exosomes are tiny bubble type structures found in most biological fluids that contain proteins and other substances including messenger-RNA. Apart from other functions, exosomes appear to be involved in cell-to-cell communication within the body.  This makes exosomes a promising target for possible use as diagnostic or screening biomarkers for any number of diseases including pancreatic cancer.

The question of whether exosomes carry full DNA has been unknown, though there have been isolated discoveries of mitochondrial and single strand DNA.

Now comes what seems to be a rather important finding by Kalluri and colleagues from MD Anderson Cancer Center in Houston, together with German colleagues in an article E-published on January 7, 2014 in the Journal of Biological Chemistry, the official publication of The American Society for Biochemistry and Molecular Biology. The researchers studied exosomes that were isolated from two pancreatic cancer cell lines, in addition to exosomes from the serum of patients with pancreatic cancer and those of healthy human controls.

They looked for and were able to find large fragments of double-stranded DNA in these exosomes involved in pancreatic cancer (adenocarcinoma). This appears to be a breakthrough.  Additionally, they found that the entire patient DNA was represented in the pancreatic cancer related exosome samples. And further, critically, that the DNA in the exosomes from the serum of patients with pancreatic cancer showed mutations involving two of the most common mutated genes in pancreatic cancer: K-Ras and p53.

This appears to be a rather startling discovery.  It needs replication and further research; these are early days.  But this line of inquiry may represent a key way station on the route to an effective diagnostic and even screening biomarker for pancreatic cancer.

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Dale O’Brien, MD

Engineered Nano-delivery of Gemcitabine for Cancer of the Pancreas (in Mice)

Normally, we do not address pre-clinical studies for pancreatic cancer in the Pancreatica Blog as so many of these fail when finally subjected to human testing. But sometimes there are such studies that are so intriguing that they cannot be easily ignored. And this particular research study of nanotherapy for the treatment of pancreatic cancer is one of them. And it ties in with another recent of our Blog articles.

Nanotechnology in this context is a term that refers to applying designed miniaturized technology to the “molecular” level of a biological system.

In this current study Nel and his colleagues at UCLA created a two-stage nano system designed to help defeat the substantive stromal protection of adenocarcinoma of the pancreas, thereby delivering a higher concentration of chemotherapy to the pancreatic tumor.  Their work was published in the November 26th 2013 issue of the journal ACS Nano, a publication not of the American Cancer Society – but of the American Chemical Society.

The first step is that the researchers developed a PEGylated liposome to carry gemcitabine to the actual pancreatic cancer tumor body – the liposome here is a bubble-like structure involving polyethylene glycol as a carry and releasing agent.  These structures proved too large to easily penetrate the pancreatic tumor stromal tissue. So, the researchers next found a way to confound the TGF-β (Transforming Growth Factor beta) signaling pathway – which helps regulate the size and integrity of tumor vascular fenestrations involving the stroma.  This was accomplished through applying a complex created by the marriage of polyethylene glycol (PEG)-coated mesoporous silica nanoparticles together with the known TGF-β inhibitor, LY364947. This effectively enlarged the fenestrations such that now the liposomes were able to relatively freely penetrate the pancreatic cancer stromal tissue.

The system was subsequently employed in mice – resulting in effects that demonstrated faster and more adenocarcinoma tumor-concentrated (efficient) gemcitabine levels, reduced apparent systemic toxicity of gemcitabine (by murine body weight, blood chemistry, and histology), and most importantly a rather dramatic reduction of the pancreatic cancer tumor burden (as determined by tumor weight) which effect especially became increasingly significant beginning at about day 25 of the treatment regimen.

This is a most interesting study.  It speaks to the problem of stroma – one of the known obstacles for chemotherapy in pancreatic cancer.  Additionally, this kind of approach would presumably be more intrinsically efficient and reduce the attendant side-effects of the chemotherapy.  There will likely for now be more pre-clinical studies.  And one day, perhaps early clinical trials?

 

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Dale O’Brien, MD

Results in on Double Punch Vaccine: Why the FDA Granted Orphan Status to CRS-207 + GVAX in Pancreatic Cancer this Past Fall

A quick note related to an earlier Pancreatica blog posting from October 24, 2013.

At the 2014 Gastrointestinal Cancers Symposium in San Francisco (January 16-18) as hosted by the American Society of Clinical Oncology (ASCO), the results of an interesting vaccine study for pancreatic cancer were released.

By way of background in the fall 2013, the U.S. Food and Drug Administration (FDA) had granted orphan drug status to the sequential double immunotherapy (vaccine) combination of CRS-207 plus GVAX – without giving openly available data as to the reason for the approval of this regimen for advanced pancreatic cancer.

These results were forthcoming at January’s ASCO Gastrointestinal Cancers Symposium.  This was the product of a Phase II study by Johns Hopkins researchers comparing the results of a single vaccine (GVAX) with those of CRS-207, a live but attenuated Listeria monocytogenes strain aimed at mesothelin plus GVAX, a biologic that stimulates the immune system’s granulocyte-macrophage colony-stimulating factor (GM-CSF).

This vaccine combination demonstrated a median overall survival of 6.1 months for patients with metastatic pancreatic cancer which compared favorably to those who received GVAX alone (3.9 months). Also, the one-year survival rate was 24% for patients with the combination in contrast with 12% of those treated with GVAX only.

Additionally, there was a kind of dose-response effect in that overall survival was increased for those patients with metastatic pancreatic cancer who received three or more doses of the combination vaccine (9.7 months) versus those who received less (4.6 months). And the tumor marker CA19-9 improved significantly in greater a greater number of patients who received the combination vaccine.

Finally, the researchers noted that the side effects of the double vaccine tended to be mild, tolerable, and rather easily resolvable.

One point that should probably be noted is that some of the Johns Hopkins researchers appear to have a financial interest related to these drug agents or in the company that supports them: Aduro BioTech Inc. of Berkeley, California.

These results do not yet appear to be published but there is a bit More Here

Dale O’Brien, MD

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