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?
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
A majority of cases of pancreatic cancer are diagnosed in advanced stage. The main reason is that early stage disease tends to have no symptoms, or vague symptoms. And there is no good screening test for early pancreatic cancer, or a simple diagnostic indicator. The two biomarkers most often used with pancreatic cancer are CA19-9 and carcinoembryonic antigen (CEA). However these assays are not very specific or sensitive in the early stages of the disease progression.
There have been a number of recent forays in terms of diagnostic biomarkers for adenocarcinoma of the pancreas based on specific gene mutations that tend to be seen in pancreatic cancer. And this has extended to the realm of MicroRNAs (or MiRNAs), small non-coding RNA strands that regulate the expression of specific referent genes. There have been a number of recent published studies demonstrating that certain members of the family of MiRNAs are affected by or affect many aspects of the natural history pancreatic cancer.
Now comes a study led by Danish researcher Johansen of Herlev Hospital near to Copenhagen (and her colleagues) which evaluates MiRNA panels as potential diagnostic markers for pancreatic cancer. The study, published in the Journal of the American Medical Association on January 22, 2014, is a case control study including 409 patients diagnosed with pancreatic cancer from six Danish hospitals from 2008 until 2012. The researchers looked at MiRNA in the whole blood of the patients with pancreatic cancer, in 25 with pancreatitis, and in 312 healthy controls. They evaluated 754 MiRNas, discovering 38 that appeared to identify pancreatic cancer. 19 of these MiRNAs were validated by a different method. Then two diagnostic panels (indices) consisting of these miRNAs were developed.
The area under the curve (AUC) for both MiRNa indices were higher than the AUC for CA19-9 (except in the validation cohort). This is an indication that these panels held improved diagnostic ability over CA19-9. Also, and perhaps importantly, including the CA19-9 together with the MiRNA indices gave better results than using CA19-9 alone.
There are serious limitations of this study. First, the differences between the AUC of the MiRNA indices and that of CA19-9 were quite small – and may not be clinically significant. Also, the age of the healthy control subjects was younger than those with pancreatic cancer.
Nevertheless, this is an intriguing finding in a clever study that requires validation and additional scientific investigation.
Dale O’Brien, MD